Neurodegenerative diseases associated with mitochondrial DNA mutations.

Young M.L., Franklin J.L.

Oxidative stress, likely stemming from dysfunctional mitochondria, occurs before major cognitive deficits and neuropathologies become apparent in Alzheimer's disease (AD) patients and in mouse models of the disease. We previously reported that treating 2- to 7-month-old 3xTg-AD mice with the mitochondria-targeted antioxidant MitoQ (mitoquinone mesylate: [10-(4,5-Dimethoxy-2-methyl-3,6-dioxo-1,4-cyclohexadien-1-yl)decyl](triphenyl)phosphonium methanesulfonate), a period when AD-like pathologies first manifest in them, prevents AD-like symptoms from developing. To elucidate further a role for mitochondria-derived oxidative stress in AD progression, we examined the ability of MitoQ to inhibit AD-like pathologies in these mice at an age in which cognitive and neuropathological symptoms have fully developed. 3xTg-AD female mice received MitoQ in their drinking water for five months beginning at twelve months after birth. Untreated 18-month-old 3xTg-AD mice exhibited significant learning deficits and extensive AD-like neuropathologies. MitoQ-treated mice showed improved memory retention compared to untreated 3xTg-AD mice as well as reduced brain oxidative stress, synapse loss, astrogliosis, microglial cell proliferation, Aβ accumulation, caspase activation, and tau hyperphosphorylation. Additionally, MitoQ treatment significantly increased the abbreviated lifespan of the 3xTg-AD mice. These findings support a role for the involvement of mitochondria-derived oxidative stress in the etiology of AD and suggest that mitochondria-targeted antioxidants may lessen symptoms in AD patients.

Takahashi M., Takahashi K.

Mitochondrial function has been closely associated with normal aging and age-related diseases. Age-associated declines in mitochondrial function, such as changes in oxygen consumption rate, cytochrome c oxidase activity of complex IV, and mitochondrial coenzyme Q (CoQ) levels, begin as early as 12 to 15 months of age in male mouse brains. Brain mitochondrial dysfunction is accompanied by increased accumulation of phosphorylated α-synuclein in the motor cortex and impairment of motor activities, which are similar characteristics of Parkinson’s disease. However, these age-associated defects are completely rescued by the administration of exogenous CoQ10 to middle-aged mice via its water solubilization by emulsification in drinking water. Further efforts to develop strategies to enhance the biological availability of CoQ10 to successfully ameliorate age-related brain mitochondrial dysfunction or neurodegenerative disorders may provide a promising anti-aging agent.

Musicco C., Cormio G., Pesce V., Loizzi V., Cicinelli E., Resta L., Ranieri G., Cormio A.

Type I endometrial cancer (EC) is the most common form of EC, displaying less aggressive behavior than type II. The development of type I endometrial cancer is considered a multistep process, with slow progression from normal endometrium to hyperplasia, the premalignant form, and endometrial cancer as a result of an unopposed estrogenic stimulation. The role of mitochondria in type I EC tumor progression and prognosis is currently emerging. This review aims to explore mitochondrial alterations in this cancer and in endometrial hyperplasia focusing on mitochondrial DNA mutations, respiratory complex I deficiency, and the activation of mitochondrial quality control systems. A deeper understanding of altered mitochondrial pathways in type I EC could provide novel opportunities to discover new diagnostic and prognostic markers as well as potential therapeutic targets.

Kozin M.S., Kulakova O.G., Favorova O.O.

Functional disruption and neuronal loss followed by progressive dysfunction of the nervous system underlies the pathogenesis of numerous disorders defined as “neurodegenerative diseases”. Multiple sclerosis, a chronic inflammatory demyelinating disease of the central nervous system resulting in serious neurological dysfunctions and disability, is one of the most common neurodegenerative diseases. Recent studies suggest that disturbances in mitochondrial functioning are key factors leading to neurodegeneration. In this review, we consider data on mitochondrial dysfunctions in multiple sclerosis, which were obtained both with patients and with animal models. The contemporary data indicate that the axonal degeneration in multiple sclerosis largely results from the activation of Ca2+-dependent proteases and from misbalance of ion homeostasis caused by energy deficiency. The genetic studies analyzing association of mitochondrial DNA polymorphic variants in multiple sclerosis suggest the participation of mitochondrial genome variability in the development of this disease, although questions of the involvement of individual genomic variants are far from being resolved.

Martínez M.S., García A., Luzardo E., Chávez-Castillo M., Olivar L.C., Salazar J., Velasco M., Quintero J.J., Bermúdez V.

Cardiac muscle contraction is a strictly regulated process which conjugates a series of electrophysiological, biochemical and mechanic events, resulting in the pumping of blood to all bodily tissues.These phenomena require a very high energetic demand both for generating the necessary mechanical force, and for maintaining cellular homeostasis during the process.In the myocardium, fatty acids (FA) represent the main energy substrate, although other secondary substrates, such as glucose and ketone bodies, may also be used.Nevertheless, under certain conditions such as heart failure or myocardial ischemia, FA metabolism may become deleterious via mechanisms such as oxidative stress and arrhythmogenesis.In an ischemic milieu, various metabolic changes occur as a consequence of hypoxia, favoring cell necrosis, ventricular arrhythmias, and death.Major events in this context include an increase in extracellular K + , a decrease in pH, and accumulation of intracellular calcium.This review includes a detailed description of the molecular basis underlying myocardial contraction and energetic metabolism in cardiomyocytes, aiming to promote an integral understanding of the pathophysiology of heart ischemia.This in turn may aid in the development of future, more satisfactory alternative treatments in the management of acute coronary ischemia episodes.

Sazonova M.A., Ryzhkova A.I., Sinyov V.V., Galitsyna E.V., Orekhova V.A., Melnichenko A.A., Orekhov A.N., Ravani A.L., Sobenin I.A.

Aim:The aim of the present article was the detection of threshold heteroplasmy level of mitochondrial DNA mutations, above which a patient is at increased risk of atherosclerotic lesions.Besides, this parameter was detected for mutations, in which after reaching threshold heteroplasmy level, a protective antiatherogenic effect started to appear.Methods: The participants of the study were 700 women and men from the Moscow region.Fragments of DNA, amplified by polymerase chain reaction, were analyzed with pyrosequencing technology.Then on the basis of pyrograms' peaks in the samples, the heteroplasmy level of the investigated mitochondrial genome mutations was detected.Results: The threshold heteroplasmy level of 11 investigated mutations (m.5178C>A, m.15059G>A, m.652delG, m.13513G>A, m.14846G>A, m.652insG, m.12315G>A, m.3336T>C, m.1555A>G, m.14459G>A, m.3256C>T) in individuals with atherosclerotic plaques or thickening of the intima-medial layer of carotid arteries was detected.Conclusion: Using the method developed in our laboratory, the authors managed to determine threshold heteroplasmy levels of 11 mitochondrial genome mutations associated

Sinyov V.V., Sazonova M.A., Ryzhkova A.I., Galitsyna E.V., Melnichenko A.A., Postnov A.Y., Orekhov A.N., Grechko A.V., Sobenin I.A.

Aim:The aim of this pilot study was to compare the heteroplasmy levels of specific mitochondrial (mt)DNA mutations in human buccal epithelial and whole blood cells in participants with different degrees of predisposition to atherosclerosis.The potential for buccal epithelium to be used for the genetic diagnosis of atherosclerosis using mtDNA mutations was assessed.Methods: Samples of buccal epithelial and whole blood cells were obtained from 134 donors.DNA was extracted from the samples and subjected to polymerase chain reaction and pyrosequencing.The threshold heteroplasmy levels of the mutations m.12315G>A, m.3336T>C, m.1555А>G, m.13513G>A, and m.3256C>T were analyzed in order to assess the potential for using buccal epithelium and whole blood for the genetic diagnosis of atherosclerosis.Results: The threshold heteroplasmy levels of the assessed mitochondrial mutations did not significantly differ between buccal epithelial and whole blood cells.Conclusion: Buccal epithelial cells may be preferable to whole blood cells for analyzing the association of mitochondrial genome mutations with atherosclerosis.

Hung K., Calkins M.J.

Neurodegeneration and mitochondrial dysfunction are closely linked across many clinical conditions. In genetic diseases that result from defects in mitochondrial DNA (mtDNA) synthesis or maintenance, neurodegeneration is a frequent and major component of the disease pathology. In sporadic neurodegenerative diseases such as Alzheimer's and Parkinson's disease, mtDNA defects have been observed clinically. Mitochondrial stress related to mtDNA dysregulation can produce neuronal dysfunction and death via impaired electron transport chain activity, which results in deficient ATP production and related increases in mitochondrial reactive oxygen species (ROS) production. However, mtDNA dysregulation in post-mitotic neurons may also produce disturbances in mitochondrial homeostasis that are known to impair neuronal function as well. In this study, we used sub-toxic doses of ethidium bromide (EtBr) to induce mtDNA-associated mitochondrial stress in primary cortical neurons and measured several aspects of mitochondrial homeostasis, mitochondrial function and cell death. We found that low-dose EtBr severely depletes mtDNA synthesis and mitochondrial mRNA levels. Furthermore, homeostatic processes are especially disrupted in toxin treated neurons while mitochondrial function is relatively preserved. Mitochondria become fragmented and motility is abolished, while respiration and mitochondrial polarization are partially maintained. Moreover at these doses, cells do not exhibit increased ROS production, clear neurite retraction or loss of viability. These results indicate that mitochondrial homeostasis is a sensitive marker of mtDNA associated stress compared to mitochondria-functional outputs or endpoints related to cellular toxicity. These homeostatic disruptions are expected to contribute to neuronal dysfunction and potentially drive neurodegenerative disease pathology.

Akbar M., Essa M.M., Daradkeh G., Abdelmegeed M.A., Choi Y., Mahmood L., Song B.

Mitochondria are important for providing cellular energy ATP through the oxidative phosphorylation pathway. They are also critical in regulating many cellular functions including the fatty acid oxidation, the metabolism of glutamate and urea, the anti-oxidant defense, and the apoptosis pathway. Mitochondria are an important source of reactive oxygen species leaked from the electron transport chain while they are susceptible to oxidative damage, leading to mitochondrial dysfunction and tissue injury. In fact, impaired mitochondrial function is commonly observed in many types of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, alcoholic dementia, brain ischemia-reperfusion related injury, and others, although many of these neurological disorders have unique etiological factors. Mitochondrial dysfunction under many pathological conditions is likely to be promoted by increased nitroxidative stress, which can stimulate post-translational modifications (PTMs) of mitochondrial proteins and/or oxidative damage to mitochondrial DNA and lipids. Furthermore, recent studies have demonstrated that various antioxidants, including naturally occurring flavonoids and polyphenols as well as synthetic compounds, can block the formation of reactive oxygen and/or nitrogen species, and thus ultimately prevent the PTMs of many proteins with improved disease conditions. Therefore, the present review is aimed to describe the recent research developments in the molecular mechanisms for mitochondrial dysfunction and tissue injury in neurodegenerative diseases and discuss translational research opportunities.

Bhat A.H., Dar K.B., Anees S., Zargar M.A., Masood A., Sofi M.A., Ganie S.A.

Mitochondria is one of the main source of oxidative stress (ROS), as it utilizes the oxygen for the energy production. ROS and RNS are normally generated by tightly regulated enzymes. Excessive stimulation of NAD(P)H and electron transport chain leads to the overproduction of ROS, results in oxidative stress, which is a good mediator to injure the cell structures, lipids, proteins, and DNA. Various oxidative events implicated in many diseases due to oxidative stress include alteration in mitochondrial proteins, mitochondrial lipids and mitochondrial DNA, Which in turn leads to the damage to nerve cell as they are metabolically very active. ROS/RNS at moderate concentrations also play roles in normal physiology of many processes like signaling pathways, induction of mitogenic response and in defense against infectious pathogens. Oxidative stress has been considered to be the main cause in the etiology of many diseases, which includes Parkinson's and Alzheimer diseases. Several PD associated genes have been found to be involved in mitochondrial function, dynamics and morphology as well. This review includes source of free radical generation, chemistry and biochemistry of ROS/RNS and mitochondrial dysfunction and the mechanism involved in neurodegenerative diseases.

Oyewole A.O., Birch‐Machin M.A.

Redox homeostasis is maintained by the antioxidant defense system, which is responsible for eliminating a wide range of oxidants, including reactive oxygen species (ROS), lipid peroxides, and metals. Mitochondria‐localized antioxidants are widely studied because the mitochondria, the major producers of intracellular ROS, have been linked to the cause of aging and other chronic diseases. Mitochondria‐targeted antioxidants have shown great potential because they cross the mitochondrial phospholipid bilayer and eliminate ROS at the heart of the source. Growing evidence has identified mitochondria‐targeted antioxidants, such as MitoQ and tiron, as potentially effective antioxidant therapies against the damage caused by enhanced ROS generation. This literature review summarizes the current knowledge on mitochondria‐targeted antioxidants and their contribution to the body's antioxidant defense system. In addition to addressing the concerns surrounding current antioxidant strategies, including difficulties in targeting antioxidant treatment to sites of pathologic oxidative damage, we discuss promising therapeutic agents and new strategic approaches.—Oyewole, A. O., BirchMachin, M. A. Mitochondria‐targeted antioxidants. FASEB J. 29, 4766–4771 (2015). www.fasebj.org

Wu W., Xu H., Wang Z., Mao Y., Yuan L., Luo W., Cui Z., Cui T., Wang X.L., Shen Y.H.

Mitochondrial injury and dysfunction, a significant feature in metabolic syndrome, triggers endothelial cell dysfunction and cell death. Increasing evidence suggests that mitophagy, a process of autophagic turnover of damaged mitochondria, maintains mitochondrial integrity. PINK1 (phosphatase and tensin homolog (PTEN)-induced putative kinase 1) and Parkin signaling is a key pathway in mitophagy control. In this study, we examined whether this pathway could protect mitochondria under metabolic stress. We found that palmitic acid (PA) induced significant mitophagy and activated PINK1 and Parkin in endothelial cells. Knocking down PINK1 or Parkin reduced mitophagy, leading to impaired clearance of damaged mitochondria and intracellular accumulation of mitochondrial fragments. Furthermore, PINK1 and Parkin prevented PA-induced mitochondrial dysfunction, ROS production and apoptosis. Finally, we show that PINK1 and Parkin were up-regulated in vascular wall of obese mice and diabetic mice. Our study demonstrates that PINK1-Parkin pathway is activated in response to metabolic stress. Through induction of mitophagy, this pathway protects mitochondrial integrity and prevents metabolic stress-induced endothelial injury.

Xiong W., Xu K., Sun J.K., Liu S., Zhao B., Shi J., Herrup K., Chow H., Lu L., Li J.

AbstractMaintaining mitochondrial homeostasis is crucial for cell survival and organismal health, as evidenced by the links between mitochondrial dysfunction and various diseases, including Alzheimer’s disease (AD). Here, we report that lncMtDloop, a non-coding RNA of unknown function encoded within the D-loop region of the mitochondrial genome, maintains mitochondrial RNA levels and function with age. lncMtDloop expression is decreased in the brains of both human AD patients and 3xTg AD mouse models. Furthermore, lncMtDloop binds to mitochondrial transcription factor A (TFAM), facilitates TFAM recruitment to mtDNA promoters, and increases mitochondrial transcription. To allow lncMtDloop transport into mitochondria via the PNPASE-dependent trafficking pathway, we fused the 3’UTR localization sequence of mitochondrial ribosomal protein S12 (MRPS12) to its terminal end, generating a specified stem-loop structure. Introducing this allotropic lncMtDloop into AD model mice significantly improved mitochondrial function and morphology, and ameliorated AD-like pathology and behavioral deficits of AD model mice. Taken together, these data provide insights into lncMtDloop as a regulator of mitochondrial transcription and its contribution to Alzheimer’s pathogenesis

Xiong W., Xu K., Sun J.K., Liu S., Zhao B., Shi J., Herrup K., Chow H., Lu L., Li J.

AbstractMaintaining mitochondrial homeostasis stands as a critical factor for cell survival and the health of organisms, as evidenced by the links between mitochondrial dysfunction and a spectrum of diseases, including Alzheimer’s disease (AD). Here we report thatlncMtDloop, a lncRNA originating from the mtDNA D-loop, upholds mitochondrial homeostasis.LncMtDloopdemonstrates an affinity for mitochondrial transcription factor A (TFAM), thereby facilitating TFAM’s recruitment to mtDNA promoters and enhancing gene transcription. We further observed decreasedlncMtDloopexpression in the brains of human AD patients and 3xTg mice. Through the introduction of allotropiclncMtDloopwith the 3’UTR ofMRPS12, a significant improvement in mitochondrial homeostasis and a concurrent amelioration of AD-like pathology were found, which exerts a positive influence on synaptic plasticity and behavioral deficits observed in AD mice. Our study provides mechanistic insights intolncMtDloopas a regulator of mitochondrial homeostasis, shedding light on a perspective regarding its contribution to Alzheimer’s pathogenesis.

Ding B., Zhang X., Wan Z., Tian F., Ling J., Tan J., Peng X.

Noninvasive diagnosis of Alzheimer’s disease (AD) is important for patients. Significant differences in the methylation of mitochondrial DNA (mtDNA) were found in AD brain tissue. Cell-free DNA (cfDNA) is a noninvasive and economical diagnostic tool. We aimed to characterize mtDNA methylation alterations in the plasma cfDNA of 31 AD patients and 26 age- and sex-matched cognitively normal control subjects. We found that the mtDNA methylation patterns differed between AD patients and control subjects. The mtDNA was predominantly hypomethylated in the plasma cfDNA of AD patients. The hypomethylation sites or regions were mainly located in mt-rRNA, mt-tRNA, and D-Loop regions. The hypomethylation of the D-Loop region in plasma cfDNA of AD patients was consistent with that in previous studies. This study presents evidence that hypomethylation in the non-protein coding region of mtDNA may contribute to the pathogenesis of AD and potential application for the diagnosis of AD.

Ben Salem N., Boussetta S., de Rojas I., Moreno-Grau S., Montrreal L., Mokni N., Mahmoud I., Younes S., Daouassi N., Frih-Ayed M., Hammami A., Ben Ammar Elgaaied A., Ruiz A., Cherni L.

Alzheimer’s disease (AD) is the most common neurodegenerative disorder in humans and presents a major health problem throughout the world. The etiology of AD is complex, and many factors are implicated, including mitochondria. Mitochondrial alteration has been proposed as a possible cause of AD. Therefore, several studies have focused on finding an association between inherited mitochondrial DNA variants and AD onset. In this study, we looked, for the first time, for a potential association between mitochondrial haplogroups or polymorphisms and AD in the Tunisian population. We also evaluated the distribution of the major genetic risk factor for AD, the apolipoprotein E epsilon 4 (APOE ε4), in this population. In total, 159 single-nucleotide polymorphisms (SNPs) of mitochondrial DNA haplogroups were genotyped in 254 individuals (58 patients and 196 controls). An additional genotyping of APOE ε4 was performed. No significant association between mitochondrial haplogroups and AD was found. However, two individual SNPs, A5656G (p = 0.03821, OR = 10.46) and A13759G (p = 0.03719, OR = 10.78), showed a significant association with AD. APOE 4 was confirmed as a risk factor for AD (p = 0.000014). Our findings may confirm the absence of a relation between mitochondrial haplogroups and AD and support the possible involvement of some inherited variants in the pathogenicity of AD.

Marde V.S., Tiwari P.L., Wankhede N.L., Taksande B.G., Upaganlawar A.B., Umekar M.J., Kale M.B.

Over the last decade, aggregating evidences suggested that there is a causative link between mutation in gene associated with mitochondrial dysfunction and development of several neurodegenerative disorders. Recent structural and functional studies associated with mitochondrial genes have shown that mitochondrial abnormalities possibly lead to mitochondrial dysfunction. Several studies on animal models of neurodegenerative diseases and mitochondrial genes have provided compelling evidence that mitochondria is involved in the initiation as well as progression of diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), and Friedreich ataxia (FA). In this mini-review, we have discussed the different etiologic and pathogenesis connected with the mitochondrial dysfunction and relevant neurodegenerative diseases that underlie the dominant part of mitochondrial genes in the disease development and its progress.

Singh G., Rao D., Kumar A.

Disorders of the central nervous system are worldwide causes of morbidity and mortality. Neurological disorders pose a large burden on worldwide health. The Global Burden of Disease Study shows that the neurological disorders such as Alzheimer's and other dementias, Parkinson's disease, multiple sclerosis, epilepsy, muscular dystrophy, and headache disorders represent 3% of the worldwide. Neurological disorders are defined as an inappropriate or impaired function of the peripheral or CNS due to impaired electrical impulses throughout the nervous system that may show the heterogeneous symptoms according to the parts of the system, which is involved in these pathologic processes. Some growing evidence on brain inflammation, viral or bacterial infection, and genetic components of neurological disease has been collected during recent years. On the basis of this evidence, we focused on the association of brain inflammation, viral or bacterial infection, mitochondrial gene, and other genetic components or mutations with neurological disorders.

Chadha S., Behl T., Sehgal A., Kumar A., Bungau S.

Brain is a fully differentiated organ and is sensitive towards oxidative damage of various compounds including lipids, proteins, and DNA that occurs during process of normal aging and is mainly due to its high energy metabolism and reduced activity of anti-oxidative defense mechanism. Mitochondria are dynamic ATP-generating organelles which constitutes cellular functions such as regulation of intracellular calcium, bio-energetic processes, and reduction-oxidation of cells. Such functioning is negatively affected due to the presence of amyloid β peptide (Aβ) which is involved in pathogenesis of Alzheimer disease (AD). Aβ interacts with mitochondria and leads to mitochondrial dysfunction. Mitochondrial dysfunction, abnormal interactions, oxidative stress, and mis-folding of synaptic proteins inside nervous system are explored and regarded as primary or initial features in insurgence of pathology (AD and other neurological disease). The major histopathological hallmarks of AD are characterized by presence of these hallmarks intracellularly, its further progression and exacerbation which leads to excessive accumulation of oligomeric as well as fibrillar-β-amyloid peptides (present extracellularly) and accumulation of neurofibrillary tangles intracellularly. The current review will focus on alterations and variation in mitochondria/mitochondrial DNA (mtDNA) and the rationale for involvement of related abnormalities in pathogenesis of AD.

Sobenin I.A., Sukhorukov V.N.