Mitochondrial Dysfunction in Aging and Cancer

O'Hara R., Tedone E., Ludlow A., Huang E., Arosio B., Mari D., Shay J.W.

Mitochondria are involved in a number of diverse cellular functions, including energy production, metabolic regulation, apoptosis, calcium homeostasis, cell proliferation, and motility, as well as free radical generation. Mitochondrial DNA (mtDNA) is present at hundreds to thousands of copies per cell in a tissue-specific manner. mtDNA copy number also varies during aging and disease progression and therefore might be considered as a biomarker that mirrors alterations within the human body. Here, we present a new quantitative, highly sensitive droplet digital PCR (ddPCR) method, droplet digital mitochondrial DNA measurement (ddMDM), to measure mtDNA copy number not only from cell populations but also from single cells. Our developed assay can generate data in as little as 3 h, is optimized for 96-well plates, and also allows the direct use of cell lysates without the need for DNA purification or nuclear reference genes. We show that ddMDM is able to detect differences between samples whose mtDNA copy number was close enough as to be indistinguishable by other commonly used mtDNA quantitation methods. By utilizing ddMDM, we show quantitative changes in mtDNA content per cell across a wide variety of physiological contexts including cancer progression, cell cycle progression, human T cell activation, and human aging.

Qian W., Kumar N., Roginskaya V., Fouquerel E., Opresko P.L., Shiva S., Watkins S.C., Kolodieznyi D., Bruchez M.P., Van Houten B.

Significance It is highly controversial whether secondary reactive oxygen species generated by dysfunctional mitochondria are able to diffuse across the cytoplasm to the nucleus and cause subsequent nuclear changes. We have developed a targeted chemoptogenetic technology to induce mitochondrial dysfunction by generating short-lived highly reactive singlet oxygen exclusively in the mitochondria, with precise spatiotemporal control by light stimulation. Through careful analysis of the events involving mitochondrial dysfunction and subsequent nuclear oxidative stress that resulted in specific telomere damage, we delineated the mechanism of mitochondria–telomere axis of cellular damage. Our findings revealed a fundamental mechanism underlying the pathophysiological role of mitochondrial singlet oxygen, with important ramifications for understanding the role of mitochondrial signaling in aging and cancer among other human diseases.

Gammage P.A., Frezza C.

Perturbed mitochondrial bioenergetics constitute a core pillar of cancer-associated metabolic dysfunction. While mitochondrial dysfunction in cancer may result from myriad biochemical causes, a historically neglected source is that of the mitochondrial genome. Recent large-scale sequencing efforts and clinical studies have highlighted the prevalence of mutations in mitochondrial DNA (mtDNA) in human tumours and their potential roles in cancer progression. In this review we discuss the biology of the mitochondrial genome, sources of mtDNA mutations, and experimental evidence of a role for mtDNA mutations in cancer. We also propose a ‘metabolic licensing’ model for mtDNA mutation-derived dysfunction in cancer initiation and progression.

Carrer A., Trefely S., Zhao S., Campbell S.L., Norgard R.J., Schultz K.C., Sidoli S., Parris J.L., Affronti H.C., Sivanand S., Egolf S., Sela Y., Trizzino M., Gardini A., Garcia B.A., et. al.

Abstract Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis, and new strategies for prevention and treatment are urgently needed. We previously reported that histone H4 acetylation is elevated in pancreatic acinar cells harboring Kras mutations prior to the appearance of premalignant lesions. Because acetyl-CoA abundance regulates global histone acetylation, we hypothesized that altered acetyl-CoA metabolism might contribute to metabolic or epigenetic alterations that promote tumorigenesis. We found that acetyl-CoA abundance is elevated in KRAS-mutant acinar cells and that its use in the mevalonate pathway supports acinar-to-ductal metaplasia (ADM). Pancreas-specific loss of the acetyl-CoA–producing enzyme ATP-citrate lyase (ACLY) accordingly suppresses ADM and tumor formation. In PDA cells, growth factors promote AKT–ACLY signaling and histone acetylation, and both cell proliferation and tumor growth can be suppressed by concurrent BET inhibition and statin treatment. Thus, KRAS-driven metabolic alterations promote acinar cell plasticity and tumor development, and targeting acetyl-CoA–dependent processes exerts anticancer effects. Significance: Pancreatic cancer is among the deadliest of human malignancies. We identify a key role for the metabolic enzyme ACLY, which produces acetyl-CoA, in pancreatic carcinogenesis. The data suggest that acetyl-CoA use for histone acetylation and in the mevalonate pathway facilitates cell plasticity and proliferation, suggesting potential to target these pathways. See related commentary by Halbrook et al., p. 326. This article is highlighted in the In This Issue feature, p. 305

Najjar Y.G., Menk A.V., Sander C., Rao U., Karunamurthy A., Bhatia R., Zhai S., Kirkwood J.M., Delgoffe G.M.

The tumor microenvironment presents physical, immunologic, and metabolic barriers to durable immunotherapy responses. We have recently described roles for both T cell metabolic insufficiency as well as tumor hypoxia as inhibitory mechanisms that prevent T cell activity in murine tumors, but whether intratumoral T cell activity or response to immunotherapy varies between patients as a function of distinct metabolic profiles in tumor cells remains unclear. Here, we show that metabolic derangement can vary widely in both degree and type in patient-derived cell lines and in ex vivo analysis of patient samples, such that some cells demonstrate solely deregulated oxidative or glycolytic metabolism. Further, deregulated oxidative, but not glycolytic, metabolism was associated with increased generation of hypoxia upon implantation into immunodeficient animals. Generation of murine single-cell melanoma cell lines that lacked either oxidative or glycolytic metabolism showed that elevated tumor oxygen consumption was associated with increased T cell exhaustion and decreased immune activity. Moreover, melanoma lines lacking oxidative metabolism were solely responsive to anti-PD-1 therapy among those tested. Prospective analysis of patient sample immunotherapy revealed that oxidative, but not glycolytic, metabolism was associated with progression on PD-1 blockade. Our data highlight a role for oxygen as a crucial metabolite required for the tumor-infiltrating T cells to differentiate appropriately upon PD-1 blockade, and suggest that tumor oxidative metabolism may be a target to improve immunotherapeutic response.

Okamoto K., Seimiya H.

Telomeres, the protective structures of chromosome ends are gradually shortened by each cell division, eventually leading to senescence or apoptosis. Cancer cells maintain the telomere length for unlimited growth by telomerase reactivation or a recombination-based mechanism. Recent genome-wide analyses have unveiled genetic and epigenetic alterations of the telomere maintenance machinery in cancer. While telomerase inhibition reveals that longer telomeres are more advantageous for cell survival, cancer cells often have paradoxically shorter telomeres compared with those found in the normal tissues. In this review, we summarize the latest knowledge about telomere length alterations in cancer and revisit its rationality. Finally, we discuss the potential utility of telomere length as a prognostic biomarker.

Yu B.P., Im D.S., Choi Y.J., Kim N.D., Lee J., Im E., Jung Y.S., Chung J.H., Seo A.Y., Lee B., Chung S., Chung K.W., Lee E.K., Kim D.H., Chung H.Y.

Coll R.C., Holley C.L., Schroder K.

In the initial published version of this article, there was a mistake in the title. The correct title should be “Mitochondrial DNA synthesis fuels NLRP3 activation”. This correction does not affect the description of the results or the conclusions of this work.

Moossavi M., Parsamanesh N., Bahrami A., Atkin S.L., Sahebkar A.

Inflammasomes are large intracellular multi-protein signalling complexes that are formed in the cytosolic compartment as an inflammatory immune response to endogenous danger signals. The formation of the inflammasome enables activation of an inflammatory protease caspase-1, pyroptosis initiation with the subsequent cleaving of the pro-inflammatory cytokines interleukin (IL)-1β and proIL-18 to produce active forms. The inflammasome complex consists of a Nod-like receptor (NLR), the adapter apoptosis-associated speck-like (ASC) protein, and Caspase-1. Dysregulation of NLRP3 inflammasome activation is involved tumor pathogenesis, although its role in cancer development and progression remains controversial due to the inconsistent findings described. In this review, we summarize the current knowledge on the contribution of the NLRP3 inflammasome on potential cancer promotion and therapy.

Hoff K.E., DeBalsi K.L., Sanchez-Quintero M.J., Longley M.J., Hirano M., Naini A.B., Copeland W.C.

Mutations in mitochondrial DNA (mtDNA) have been linked to a variety of metabolic, neurological and muscular diseases which can present at any time throughout life. MtDNA is replicated by DNA polymerase gamma (Pol γ), twinkle helicase and mitochondrial single-stranded binding protein (mtSSB). The Pol γ holoenzyme is a heterotrimer consisting of the p140 catalytic subunit and a p55 homodimeric accessory subunit encoded by the nuclear genes POLG and POLG2, respectively. The accessory subunits enhance DNA binding and promote processive DNA synthesis of the holoenzyme. Mutations in either POLG or POLG2 are linked to disease and adversely affect maintenance of the mitochondrial genome, resulting in depletion, deletions and/or point mutations in mtDNA. A homozygous mutation located at Chr17: 62492543G>A in POLG2, resulting in R182W substitution in p55, was previously identified to cause mtDNA depletion and fatal hepatic liver failure. Here we characterize this homozygous R182W p55 mutation using in vivo cultured cell models and in vitro biochemical assessments. Compared to control fibroblasts, homozygous R182W p55 primary dermal fibroblasts exhibit a two-fold slower doubling time, reduced mtDNA copy number and reduced levels of POLG and POLG2 transcripts correlating with the reported disease state. Expression of R182W p55 in HEK293 cells impairs oxidative-phosphorylation. Biochemically, R182W p55 displays DNA binding and association with p140 similar to WT p55. R182W p55 mimics the ability of WT p55 to stimulate primer extension, support steady-state nucleotide incorporation, and suppress the exonuclease function of Pol γ in vitro. However, R182W p55 has severe defects in protein stability as determined by differential scanning fluorimetry and in stimulating function as determined by thermal inactivation. These data demonstrate that the Chr17: 62492543G>A mutation in POLG2, R182W p55, severely impairs stability of the accessory subunit and is the likely cause of the disease phenotype.

Zhong Z., Liang S., Sanchez-Lopez E., He F., Shalapour S., Lin X., Wong J., Ding S., Seki E., Schnabl B., Hevener A.L., Greenberg H.B., Kisseleva T., Karin M.

Dysregulated NLRP3 inflammasome activity results in uncontrolled inflammation, which underlies many chronic diseases. Although mitochondrial damage is needed for the assembly and activation of the NLRP3 inflammasome, it is unclear how macrophages are able to respond to structurally diverse inflammasome-activating stimuli. Here we show that the synthesis of mitochondrial DNA (mtDNA), induced after the engagement of Toll-like receptors, is crucial for NLRP3 signalling. Toll-like receptors signal via the MyD88 and TRIF adaptors to trigger IRF1-dependent transcription of CMPK2, a rate-limiting enzyme that supplies deoxyribonucleotides for mtDNA synthesis. CMPK2-dependent mtDNA synthesis is necessary for the production of oxidized mtDNA fragments after exposure to NLRP3 activators. Cytosolic oxidized mtDNA associates with the NLRP3 inflammasome complex and is required for its activation. The dependence on CMPK2 catalytic activity provides opportunities for more effective control of NLRP3 inflammasome-associated diseases. New mitochondrial DNA synthesis links the priming and activation of the NLRP3 inflammasome.

Leão R., Apolónio J.D., Lee D., Figueiredo A., Tabori U., Castelo-Branco P.

Limitless self-renewal is one of the hallmarks of cancer and is attained by telomere maintenance, essentially through telomerase (hTERT) activation. Transcriptional regulation of hTERT is believed to play a major role in telomerase activation in human cancers. The dominant interest in telomerase results from its role in cancer. The role of telomeres and telomere maintenance mechanisms is well established as a major driving force in generating chromosomal and genomic instability. Cancer cells have acquired the ability to overcome their fate of senescence via telomere length maintenance mechanisms, mainly by telomerase activation. hTERT expression is up-regulated in tumors via multiple genetic and epigenetic mechanisms including hTERT amplifications, hTERT structural variants, hTERT promoter mutations and epigenetic modifications through hTERT promoter methylation. Genetic (hTERT promoter mutations) and epigenetic (hTERT promoter methylation and miRNAs) events were shown to have clinical implications in cancers that depend on hTERT activation. Knowing that telomeres are crucial for cellular self-renewal, the mechanisms responsible for telomere maintenance have a crucial role in cancer diseases and might be important oncological biomarkers. Thus, rather than quantifying TERT expression and its correlation with telomerase activation, the discovery and the assessment of the mechanisms responsible for TERT upregulation offers important information that may be used for diagnosis, prognosis, and treatment monitoring in oncology. Furthermore, a better understanding of these mechanisms may promote their translation into effective targeted cancer therapies. Herein, we reviewed the underlying mechanisms of hTERT regulation, their role in oncogenesis, and the potential clinical applications in telomerase-dependent cancers.

Melber A., Haynes C.M.

The mitochondrial network is not only required for the production of energy, essential cofactors and amino acids, but also serves as a signaling hub for innate immune and apoptotic pathways. Multiple mechanisms have evolved to identify and combat mitochondrial dysfunction to maintain the health of the organism. One such pathway is the mitochondrial unfolded protein response (UPRmt), which is regulated by the mitochondrial import efficiency of the transcription factor ATFS-1 in C. elegans and potentially orthologous transcription factors in mammals (ATF4, ATF5, CHOP). Upon mitochondrial dysfunction, import of ATFS-1 into mitochondria is reduced, allowing it to be trafficked to the nucleus where it promotes the expression of genes that promote survival and recovery of the mitochondrial network. Here, we discuss recent findings underlying UPRmt signal transduction and how this adaptive transcriptional response may interact with other mitochondrial stress response pathways.

Guerra F., Guaragnella N., Arbini A.A., Bucci C., Giannattasio S., Moro L.

Epithelial-to-mesenchymal transition (EMT) allows epithelial cancer cells to assume mesenchymal features, endowing them with enhanced motility and invasiveness, thus enabling cancer dissemination and metastatic spread. The induction of EMT is orchestrated by EMT-inducing transcription factors (EMT-TFs) that switch on the expression of “mesenchymal” genes and switch off the expression of “epithelial” genes. Mitochondrial dysfunction is a hallmark of cancer and has been associated with progression to a metastatic and drug-resistant phenotype. The mechanistic link between metastasis and mitochondrial dysfunction is gradually emerging. The discovery that mitochondrial dysfunction owing to deregulated mitophagy, depletion of the mitochondrial genome (mtDNA) or mutations in Krebs’ cycle enzymes, such as succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH), activate the EMT gene signature has provided evidence that mitochondrial dysfunction and EMT are interconnected. In this review, we provide an overview of the current knowledge on the role of different types of mitochondrial dysfunction in inducing EMT in cancer cells. We place emphasis on recent advances in the identification of signaling components in the mito-nuclear communication network initiated by dysfunctional mitochondria that promote cellular remodeling and EMT activation in cancer cells.

Chaudhari S.N., Kipreos E.T.

Mitochondria are dynamic organelles that undergo fusion and fission events. Mitochondrial dynamics are required for mitochondrial viability and for responses to changes in bioenergetic status. Here we describe an insulin-signaling and SCFLIN-23-regulated pathway that controls mitochondrial fusion in Caenorhabditis elegans by repressing the expression of the mitochondrial proteases SPG-7 and PPGN-1. This pathway is required for mitochondrial fusion in response to physical exertion, and for the associated extension in lifespan. We show that diverse longevity pathways exhibit increased levels of elongated mitochondria. The increased mitochondrial fusion is essential for longevity in the diverse longevity pathways, as inhibiting mitochondrial fusion reduces their lifespans to wild-type levels. Our results suggest that increased mitochondrial fusion is not a major driver of longevity, but rather is essential to allow the survival of older animals beyond their normal lifespan in diverse longevity pathways. Mitochondria can undergo shape changes as a result of fusion and fission events. Here the authors describe how insulin signalling regulates mitochondrial fusion in C. elegans, and show that mitochondrial fusion is necessary, but not sufficient, for longevity of worms with mutations that increase lifespan.

Zhang C., Neha, Zhang J., Prashant, Li X., Mishra S.K., Fleishman J., Parvez S., Jha S.K., Huang M.

Zhang G., Lu Y., Wang Z., Ma R., Jin H., Zhang J., Liu F., Ding Y.

Pokharel M.D., Feng A., Liang Y., Ma W., Aggarwal S., Unwalla H., Black S.M., Wang T.

Sepsis is a severe and life-threatening medical syndrome that can lead to organ failure and death. Despite advances in medical treatment, current therapies are often inadequate, with high septic mortality rates. Therefore, there is a critical need for reliable prognostic markers to be used in clinical settings to improve the management and outcomes of patients with sepsis. Recent studies have suggested that mitochondrial dynamics, including the processes of mitochondrial fission and fusion, are closely related to the severity of sepsis and the status of inflammation. By monitoring transcriptomic signals related to mitochondrial dynamics, new and reliable biomarkers can be engineered to more accurately predict sepsis survival risk. Such biomarkers would be invaluable in clinical settings, aiding healthcare providers in the early identification of high-risk patients and improving treatment strategies. To achieve this goal, we utilized the major mitochondrial fission regulatory protein dynamin-related protein 1 (Drp1, gene code DNM1L) and identified Drp1-associated genes that are enriched with sepsis survival genes. A 12-gene signature (GS) was established as a differentially expressed gene (DEG)-based GS. Next, we compared genes of proteins that interact with Drp1 to sepsis survival genes and identified 7 common genes, establishing a GS we term as protein-protein interaction (PPI)-based GS. To evaluate if these GSs can predict sepsis survival, we used publicly available human blood transcriptomic datasets from sepsis patients. We confirmed that both GSs can successfully predict sepsis survival in both discovery and validation cohorts with high sensitivity and specificity, with the PPI-based GS showing enhanced prognostic performance. Together, this study successfully engineers a new and validated blood-borne biomarker (PPI-based 7-gene GS) for sepsis survival risk prediction. This biomarker holds the potential for improving the early identification of high-risk sepsis patients and optimizing personalized treatment strategies to reduce sepsis mortality.

Pahwa R., Wadhwa K., Panwar R., Sagwal J., Singh G., Tuli H.S., Gautam R.K.

Despite energy metabolism, apoptosis regulation, and cell signaling; mitochondria are also indispensably accountable for cancer initiation and progression, as affirmed by several studies. Furthermore, mitochondria are the most important site for the generation of reactive oxygen species (ROS), responsible for the preservation of redox balance; its overproduction also endorses cancer growth by modulating gene expressions and participation in various signaling pathways, thereby inducing genomic instability. Since tumor cells have long been found to reveal altered mitochondrial structure and function, thus, targeting mitochondria has emerged as a possible intervention for cancer therapies. Nonetheless, numerous stratagems have been proposed to date for selective delivery to mitochondria. Due to the low efficacy and toxicities of currently using mitochondria-targeting anticancer agents as an effective anticancer therapy, mitochondria-targeting nanotechnologies have emerged as a novel approach that has been demonstrated to be effective in cancer therapies in both in vitro and in vivo studies. Currently, numerous types of nanomaterials including polymeric, lipid, metallic, magnetic, silica, semiconductor, and graphene oxide nanoparticles have been fabricated for mitochondria-targeted cancer therapies to augment cancer cell destruction. In consistent, the present book chapter aims to abridge the possible role of mitochondrial ROS on cancer progression and gives a summary of the possibilities to target mitochondria for anticancer therapies.

Liu F., Sun X., Wei C., Ji L., Song Y., Yang C., Wang Y., Liu X., Wang D., Kang J.

AbstractMitochondria play a crucial role in numerous biological processes; however, limited methods and research have focused on revealing mitochondrial heterogeneity at the single‐cell level. In this study, we optimized the DNBelab C4 single‐cell ATAC (assay for transposase‐accessible chromatin) sequencing workflow for single‐cell mitochondrial sequencing (C4_mtscATAC‐seq). We validated the effectiveness of our C4_mtscATAC‐seq protocol by sequencing the HEK‐293T cell line with two biological replicates, successfully capturing both mitochondrial content (~68% of total sequencing data) and open chromatin status simultaneously. Subsequently, we applied C4_mtscATAC‐seq to investigate two mouse tissues, spleen and bone marrow, obtained from two mice aged 2 months and two mice aged 23 months. Our findings revealed higher mitochondrial DNA (mtDNA) content in young tissues compared to more variable mitochondrial content in aged tissues, consistent with higher activity scores of nuclear genes associated with mitochondrial replication and transcription in young tissues. We detected a total of 22, 15, and 21 mtDNA mutations in the young spleen, aged spleen, and bone marrow, respectively, with most variant allele frequencies (VAF) below 1%. Moreover, we observed a higher number of mtDNA mutations with higher VAF in aged tissues compared to young tissues. Importantly, we identified three mtDNA variations (m.9821A>T, m.15219T>C, and m.15984C>T) with the highest VAF in both aged spleen and aged bone marrow. By comparing cells with and without these mtDNA variations, we analyzed differential open chromatin status to identify potential genes associated with these mtDNA variations, including transcription factors such as KLF15 and NRF1. Our study presents an alternative single‐cell mitochondrial sequencing method and provides crude insights into age‐related single‐cell mitochondrial variations.

Zheng B., Long W., Zheng W., Zeng Y., Guo X., Chan K., She M., Leung A.S., Lu Y., Wong W.

Narayan S., Affrald. R J.

Background: Environmental factors like UV radiation and epigenetic changes are significant factors for skin cancer that trigger early aging. This review provides essential information on cancer development concerning aging, the receptors involved, and the therapeutic targets. Objective: Biopolymers like polysaccharide, polyphenols, proteins, and nucleic acid plays a vital role in the regulation of normal cell homeostasis. Therefore, it is pertinent to explore the role of biopolymers as antiaging formulations and the possibility of these formulations being used against cancer via topical administrations. Objective: Biopolymers like polysaccharide, polyphenols, proteins, and nucleic acid plays a vital role in the regulation of normal cell homeostasis. Therefore, it is pertinent to explore the role of biopolymers as antiaging formulations and the possibility of these formulations being used against cancer via topical administrations. Methods: As UV radiation is one of the predominant factors in causing skin cancer, the association of receptors between aging and cancer indicated that insulin receptor, melatonin receptor, toll-like receptor, SIRT 1 receptor, tumor-specific T cell receptor and mitochondria-based targeting could be used to direct therapeutics for suppression of cancer and prevent aging. Results: Biopolymer-based nanoformulations have tremendously progressed by entrapment of drugs like curcumin and resveratrol which can prevent cancer and aging simultaneously. Conclusion: Certain protein signaling or calcium and ROS signaling pathways are different for cancer and aging. The involvement of mitochondrial DNA mutation along with telomere shortening with a change in cellular energetics leading to genomic instability in the aging process can also induce mitochondrial dysfunction and epigenetic alterations leading to skin cancer. Therefore, the use of biopolymers as a topical supplement during the aging process can result in the prevention of cancer. Conclusion: Certain protein signaling or calcium and ROS signaling pathways are different for cancer and aging. The involvement of mitochondrial DNA mutation along with telomere shortening with a change in cellular energetics leading to genomic instability in the aging process can also induce mitochondrial dysfunction and epigenetic alterations leading to skin cancer. Therefore, the use of biopolymers as a topical supplement during the aging process can result in the prevention of cancer.

Zhu Y., Hui Q., Zhang Z., Fu H., Qin Y., Zhao Q., Li Q., Zhang J., Guo L., He W., Han C.

AbstractSynapses serve as the points of communication between neurons, consisting primarily of three components: the presynaptic membrane, synaptic cleft, and postsynaptic membrane. They transmit signals through the release and reception of neurotransmitters. Synaptic plasticity, the ability of synapses to undergo structural and functional changes, is influenced by proteins such as growth‐associated proteins, synaptic vesicle proteins, postsynaptic density proteins, and neurotrophic growth factors. Furthermore, maintaining synaptic plasticity consumes more than half of the brain's energy, with a significant portion of this energy originating from ATP generated through mitochondrial energy metabolism. Consequently, the quantity, distribution, transport, and function of mitochondria impact the stability of brain energy metabolism, thereby participating in the regulation of fundamental processes in synaptic plasticity, including neuronal differentiation, neurite outgrowth, synapse formation, and neurotransmitter release. This article provides a comprehensive overview of the proteins associated with presynaptic plasticity, postsynaptic plasticity, and common factors between the two, as well as the relationship between mitochondrial energy metabolism and synaptic plasticity.

Dong Z., Wu L., Hong H.

Oral inflammatory diseases (OIDs) include many common diseases such as periodontitis and pulpitis. The causes of OIDs consist microorganism, trauma, occlusal factors, autoimmune dis-eases and radiation therapy. When treated unproperly, such diseases not only affect oral health but also pose threat to people’s overall health condition. Therefore, identifying OIDs at an early stage and exploring new therapeutic strategies are important tasks for oral-related research. Mitochondria are crucial organelles for many cellular activities and disruptions of mitochondrial function not only affect cellular metabolism but also indirectly influence people’s health and life span. Mitochondrial dysfunction has been implicated in many common polygenic diseases, including cardiovascular and neurodegenerative diseases. Recently, increasing evidence suggests that mitochondrial dysfunction plays a critical role in the development and progression of OIDs and its associated systemic diseases. In this review, we elucidated the critical insights into mitochondrial dysfunction and its involvement in the inflammatory responses in OIDs. We also summarized recent research progresses on the treatment of OIDs targeting mitochondrial dysfunction and discussed the underlying mechanisms.

Yan M., Wang J., Wang H., Zhou J., Qi H., Naji Y., Zhao L., Tang Y., Dai Y.

Abstract Background Clear cell renal cell carcinoma (ccRCC) is closely associated with steroid hormones and their receptors affected by lipid metabolism. Recently, there has been growing interest in the carcinogenic role of NR3C1, the sole gene responsible for encoding glucocorticoid receptor. However, the specific role of NR3C1 in ccRCC remains unclear. The present study was thus developed to explore the underlying mechanism of NR3C1’s carcinogenic effects in ccRCC. Methods Expression of NR3C1 was verified by various tumor databases and assessed using RT-qPCR and western blot. Stable transfected cell lines of ccRCC with NR3C1 knockdown were constructed, and a range of in vitro and in vivo experiments were performed to examine the effects of NR3C1 on ccRCC proliferation and migration. Transcriptomics and lipidomics sequencing were then conducted on ACHN cells, which were divided into control and sh-NR3C1 group. Finally, the sequencing results were validated using transmission electron microscopy, mitochondrial membrane potential assay, immunofluorescence co-localization, cell immunofluorescent staining, and Western blot. The rescue experiments were designed to investigate the relationship between endoplasmic reticulum stress (ER stress) and mitophagy in ccRCC cells after NR3C1 knockdown, as well as the regulation of their intrinsic signaling pathways. Results The expression of NR3C1 in ccRCC cells and tissues was significantly elevated. The sh-NR3C1 group, which had lower levels of NR3C1, exhibited a lower proliferation and migration capacity of ccRCC than that of the control group (P < 0.05). Then, lipidomic and transcriptomic sequencing showed that lipid metabolism disorders, ER stress, and mitophagy genes were enriched in the sh-NR3C1 group. Finally, compared to the control group, ER stress and mitophagy were observed in the sh-NR3C1 group, while the expression of ATF6, CHOP, PINK1, and BNIP3 was also up-regulated (P < 0.05). Furthermore, Ceapin-A7, an inhibitor of ATF6, significantly down-regulated the expression of PINK1 and BNIP3 (P < 0.05), and significantly increased the proliferation and migration of ccRCC cells (P < 0.05). Conclusions This study confirms that knockdown of NR3C1 activates ER stress and induces mitophagy through the ATF6-PINK1/BNIP3 pathway, resulting in reduced proliferation and migration of ccRCC. These findings indicate potential novel targets for clinical treatment of ccRCC. Graphical Abstract

Naeini S.H., Mavaddatiyan L., Kalkhoran Z.R., Taherkhani S., Talkhabi M.

Aging is a natural process that determined by a functional decline in cells and tissues as organisms are growing old, resulting in an increase at risk of disease and death. To this end, many efforts have been made to control aging and increase lifespan and healthspan. These efforts have led to the discovery of several anti-aging drugs and compounds such as rapamycin and metformin. Recently, alpha-ketoglutarate (AKG) has been introduced as a potential anti-aging metabolite that can control several functions in organisms, thereby increases longevity and improves healthspan. Unlike other synthetic anti-aging drugs, AKG is one of the metabolites of the tricarboxylic acid (TCA) cycle, also known as the Krebs cycle, and synthesized in the body. It plays a crucial role in the cell energy metabolism, amino acid/protein synthesis, epigenetic regulation, stemness and differentiation, fertility and reproductive health, and cancer cell behaviors. AKG exerts its effects through different mechanisms such as inhibiting mTOR and ATP-synthase, modulating DNA and histone demethylation and reducing ROS formation. Herein, we summarize the recent findings of AKG-related lifespan and healthspan studies and discuss AKG associated cell and molecular mechanisms involved in increasing longevity, improving reproduction, and modulating stem cells and cancer cells behavior. We also discuss the promises and limitations of AKG for delaying aging and other potential applications.

Rickard B.P., Overchuk M., Chappell V.A., Kemal Ruhi M., Sinawang P.D., Nguyen Hoang T.T., Akin D., Demirci U., Franco W., Fenton S.E., Santos J.H., Rizvi I.

Mitochondria are regulators of key cellular processes, including energy production and redox homeostasis. Mitochondrial dysfunction is associated with various human diseases, including cancer. Importantly, both structural and functional changes can alter mitochondrial function. Morphologic and quantifiable changes in mitochondria can affect their function and contribute to disease. Structural mitochondrial changes include alterations in cristae morphology, mitochondrial DNA integrity and quantity, and dynamics, such as fission and fusion. Functional parameters related to mitochondrial biology include the production of reactive oxygen species, bioenergetic capacity, calcium retention, and membrane potential. Although these parameters can occur independently of one another, changes in mitochondrial structure and function are often interrelated. Thus, evaluating changes in both mitochondrial structure and function is crucial to understanding the molecular events involved in disease onset and progression. This review focuses on the relationship between alterations in mitochondrial structure and function and cancer, with a particular emphasis on gynecologic malignancies. Selecting methods with tractable parameters may be critical to identifying and targeting mitochondria-related therapeutic options. Methods to measure changes in mitochondrial structure and function, with the associated benefits and limitations, are summarized.

Tassone A., Meringolo M., Ponterio G., Bonsi P., Schirinzi T., Martella G.

Strong evidence suggests a correlation between degeneration and mitochondrial deficiency. Typical cases of degeneration can be observed in physiological phenomena (i.e., ageing) as well as in neurological neurodegenerative diseases and cancer. All these pathologies have the dyshomeostasis of mitochondrial bioenergy as a common denominator. Neurodegenerative diseases show bioenergetic imbalances in their pathogenesis or progression. Huntington’s chorea and Parkinson’s disease are both neurodegenerative diseases, but while Huntington’s disease is genetic and progressive with early manifestation and severe penetrance, Parkinson’s disease is a pathology with multifactorial aspects. Indeed, there are different types of Parkinson/Parkinsonism. Many forms are early-onset diseases linked to gene mutations, while others could be idiopathic, appear in young adults, or be post-injury senescence conditions. Although Huntington’s is defined as a hyperkinetic disorder, Parkinson’s is a hypokinetic disorder. However, they both share a lot of similarities, such as neuronal excitability, the loss of striatal function, psychiatric comorbidity, etc. In this review, we will describe the start and development of both diseases in relation to mitochondrial dysfunction. These dysfunctions act on energy metabolism and reduce the vitality of neurons in many different brain areas.

Bardelčíková A., Šoltys J., Mojžiš J.

Colorectal cancer (CRC) represents the second leading cause of cancer-related deaths worldwide. The pathogenesis of CRC is a complex multistep process. Among other factors, inflammation and oxidative stress (OS) have been reported to be involved in the initiation and development of CRC. Although OS plays a vital part in the life of all organisms, its long-term effects on the human body may be involved in the development of different chronic diseases, including cancer diseases. Chronic OS can lead to the oxidation of biomolecules (nucleic acids, lipids and proteins) or the activation of inflammatory signaling pathways, resulting in the activation of several transcription factors or the dysregulation of gene and protein expression followed by tumor initiation or cancer cell survival. In addition, it is well known that chronic intestinal diseases such as inflammatory bowel disease (IBD) are associated with an increased risk of cancer, and a link between OS and IBD initiation and progression has been reported. This review focuses on the role of oxidative stress as a causative agent of inflammation in colorectal cancer.

Li Z., Zou J., Chen X.

Emerging as a potent anti-cancer treatment, subcellular targeted cancer therapy has drawn increasing attention, bringing great opportunities for clinical application. In this review, we summarize two targeting strategies for four main subcellular organelles (mitochondria, lysosome, endoplasmic reticulum, and nucleus), including molecule and nanomaterial (inorganic nanoparticles, micelles, organic polymers, and others)-based targeted delivery or therapeutic strategies. Phototherapy, chemotherapy, radiotherapy, immunotherapy, and "all-in-one" combination therapy are among the strategies covered in detail. Such materials have been constructed based on the specific properties and relevant mechanisms of organelles, enabling the elimination of tumors by inducing dysfunction in the corresponding organelles or destroying specific structures. The challenges faced by organelle-targeting cancer therapies are also summarized. Looking forward, we envision a paradigm for organelle-targeting therapy with enhanced therapeutic efficacy compared to current clinical approaches. This article is protected by copyright. All rights reserved.