Accumulation Of Mitochondrial DNA Mutations Research Articles

Mitochondrial DNA mutations attenuate Bleomycin-induced dermal fibrosis by inhibiting differentiation into myofibroblasts

Post-mitotic, non-proliferative dermal fibroblasts have crucial functions in maintenance and restoration of tissue homeostasis. They are involved in essential processes such as wound healing, pigmentation and hair growth, but also tumor development and aging-associated diseases. These processes are energetically highly demanding and error prone when mitochondrial damage occurs. However, mitochondrial function in fibroblasts and the influence of mitochondrial dysfunction on fibroblast-specific demands are still unclear. To address these questions, we created a mouse model in which accelerated cell-specific mitochondrial DNA (mtDNA) damage accumulates. We crossed mice carrying a dominant-negative mutant of the mitochondrial replicative helicase Twinkle (RosaSTOP system) with mice that express fibroblast-specific Cre Recombinase (Collagen1A2 CreERT) which can be activated by Tamoxifen (TwinkleFIBRO). Thus, we are able to induce mtDNA deletions and duplications in specific cells, a process which resembles the physiological aging process in humans, where this damage accumulates in all tissues. Upon proliferation in vitro, Tamoxifen induced Twinkle fibroblasts deplete most of their mitochondrial DNA which, although not disturbing the stoichiometry of the respiratory chain complexes, leads to reduced ROS production and mitochondrial membrane potential as well as an anti-inflammatory and anti-fibrotic profile of the cells. In Sodium Azide treated wildtype fibroblasts, without a functioning respiratory chain, we observe the opposite, a rather pro-inflammatory and pro-fibrotic signature. Upon accumulation of mitochondrial DNA mutations in vivo the TwinkleFIBRO mice are protected from fibrosis development induced by intradermal Bleomycin injections. This is due to dampened differentiation of the dermal fibroblasts into α−smooth-muscle-actin positive myofibroblasts in TwinkleFIBRO mice. We thus provide evidence for striking differences of the impact that mtDNA mutations have in contrast to blunted mitochondrial function in dermal fibroblasts and skin homeostasis. These data contribute to improved understanding of mitochondrial function and dysfunction in skin and provide mechanistic insight into potential targets to treat skin fibrosis in the future.

Preserved striatal innervation maintains motor function despite severe loss of nigral dopaminergic neurons.

Degeneration of dopaminergic neurons in the substantia nigra and their striatal axon terminals causes cardinal motor symptoms of Parkinson's disease. In idiopathic cases, high levels of mitochondrial DNA alterations, leading to mitochondrial dysfunction, are a central feature of these vulnerable neurons. Here we present a mouse model expressing the K320E variant of the mitochondrial helicase Twinkle in dopaminergic neurons, leading to accelerated mitochondrial DNA mutations. These K320E-TwinkleDaN mice showed normal motor function at 20 months of age, although ∼70% of nigral dopaminergic neurons had perished. Remaining neurons still preserved ∼75% of axon terminals in the dorsal striatum and enabled normal dopamine release. Transcriptome analysis and viral tracing confirmed compensatory axonal sprouting of the surviving neurons. We conclude that a small population of substantia nigra dopaminergic neurons is able to adapt to the accumulation of mitochondrial DNA mutations and maintain motor control.

Mitochondrial dysfunction and its association with age-related disorders.

Aging is a complex process that features a functional decline in many organelles. Various factors influence the aging process, such as chromosomal abnormalities, epigenetic changes, telomere shortening, oxidative stress, and mitochondrial dysfunction. Mitochondrial dysfunction significantly impacts aging because mitochondria regulate cellular energy, oxidative balance, and calcium levels. Mitochondrial integrity is maintained by mitophagy, which helps maintain cellular homeostasis, prevents ROS production, and protects against mtDNA damage. However, increased calcium uptake and oxidative stress can disrupt mitochondrial membrane potential and permeability, leading to the apoptotic cascade. This disruption causes increased production of free radicals, leading to oxidative modification and accumulation of mitochondrial DNA mutations, which contribute to cellular dysfunction and aging. Mitochondrial dysfunction, resulting from structural and functional changes, is linked to age-related degenerative diseases. This review focuses on mitochondrial dysfunction, its implications in aging and age-related disorders, and potential anti-aging strategies through targeting mitochondrial dysfunction.

Aging-associated accumulation of mitochondrial DNA mutations in tumor origin

Abstract The majority of cancer patients are among aged population, suggesting an urgent need to advance our knowledge on complicated relationship between aging and cancer. It has been hypothesized that metabolic changes during aging could act as a driver for tumorigenesis. Given the fact that mitochondrial DNA (mtDNA) mutations are common in both tumors and aged tissues, it is interesting to contemplate possible role of age-related mtDNA mutations in tumorigenesis. MtDNA encodes genes essential for mitochondrial metabolism, and mtDNA mutates at a much higher rate than nuclear genome. Random drifting of somatic mtDNA mutations, as a result of cell division or mitochondrial turnover during aging, may lead to more and more cells harboring high-frequency pathogenic mtDNA mutations, albeit at different loci, in single-cells. Such mutations can induce metabolic reprogramming, nuclear genome instability and immune response, which might increase the likelihood of tumorigenesis. In this review, we summarize current understanding of how mtDNA mutations accumulate with aging and how these mutations could mechanistically contribute to tumor origin. We also discuss potential prevention strategies for mtDNA mutation-induced tumorigenesis, and future works needed in this direction.

Pathophysiological Mechanisms Explaining the Association Between Low Skeletal Muscle Mass and Cognitive Function

Low skeletal muscle mass is associated with cognitive impairment and dementia in older adults. This review describes the possible underlying pathophysiological mechanisms: systemic inflammation, insulin metabolism, protein metabolism, and mitochondrial function. We hypothesize that the central tenet in this pathophysiology is the dysfunctional myokine secretion consequent to minimal physical activity. Myokines, such as fibronectin type III domain containing 5/irisin and cathepsin B, are released by physically active muscle and cross the blood–brain barrier. These myokines upregulate local neurotrophin expression such as brain-derived neurotrophic factor (BDNF) in the brain microenvironment. BDNF exerts anti-inflammatory effects that may be responsible for neuroprotection. Altered myokine secretion due to physical inactivity exacerbates inflammation and impairs muscle glucose metabolism, potentially affecting the transport of insulin across the blood–brain barrier. Our working model also suggests other underlying mechanisms. A negative systemic protein balance, commonly observed in older adults, contributes to low skeletal muscle mass and may also reflect deficient protein metabolism in brain tissues. As a result of age-related loss in skeletal muscle mass, decrease in the abundance of mitochondria and detriments in their function lead to a decrease in tissue oxidative capacity. Dysfunctional mitochondria in skeletal muscle and brain result in the excessive production of reactive oxygen species, which drives tissue oxidative stress and further perpetuates the dysfunction in mitochondria. Both oxidative stress and accumulation of mitochondrial DNA mutations due to aging drive cellular senescence. A targeted approach in the pathophysiology of low muscle mass and cognition could be to restore myokine balance by physical activity.

Mitochondrial complex I subunit deficiency promotes pancreatic α-cell proliferation

ObjectiveThere is strong evidence that mitochondrial DNA mutations and mitochondrial dysfunction play a role in diabetes pathogenesis. The homozygous knock-in mtDNA mutator mouse is a model of premature aging due to the accumulation of mitochondrial DNA mutations. We used this mouse model to investigate the relationship between mitochondrial subunit expression and pancreatic islet cell composition. MethodsQuadruple immunofluorescence was used to quantify mitochondrial subunit expression (complex I and IV) and cell composition in pancreatic islets from mitochondrial DNA mutator mice (PolgAmut/mut) and control C57BL/6 mice at 12 and 44 weeks of age. ResultsMitochondrial complex I subunit expression was decreased in islets from 12 week PolgAmut/mut mice. This complex I deficiency persisted with age and was associated with decreased insulin staining intensity at 44 weeks. Complex I deficiency was greater in α-cells compared with β-cells in islets from 44 week PolgAmut/mut mice. Islet cell composition was normal in 12 week PolgAmut/mut mice, but the β: α cell ratio was decreased in islets from 44 week PolgAmut/mut mice. This was due to an increase in α-cell number linked to an increase in α-cell proliferation. ConclusionComplex I deficiency promotes α-cell proliferation and alters islet cell composition.

Mitofusin1 regulates innate immune responses by inhibiting the accumulation of mitochondrial DNA mutation in sepsis

Mitofusin1 regulates innate immune responses by inhibiting the accumulation of mitochondrial DNA mutation in sepsis

Senescent Cell Depletion Through Targeting BCL-Family Proteins and Mitochondria.

Senescent cells with replicative arrest can be generated during genotoxic, oxidative, and oncogenic stress. Long-term retention of senescent cells in the body, which is attributed to highly expressed BCL-family proteins, chronically damages tissues mainly through a senescence-associated secretory phenotype (SASP). It has been documented that accumulation of senescent cells contributes to chronic diseases and aging-related diseases. Despite the fact that no unique marker is available to identify senescent cells, increased p16INK4a expression has long been used as an in vitro and in vivo marker of senescent cells. We reviewed five existing p16INK4a reporter mouse models to detect, isolate, and deplete senescent cells. Senescent cells express high levels of anti-apoptotic and pro-apoptotic genes compared to normal cells. Thus, disrupting the balance between anti-apoptotic and pro-apoptotic gene expression, such as ABT-263 and ABT-737, can activate the apoptotic signaling pathway and remove senescent cells. Mitochondrial abnormalities in senescent cells were also discussed, for example mitochondrial DNA mutation accumulation, dysfunctional mitophagy, and mitochondrial unfolded protein response (mtUPR). The mitochondrial-targeted tamoxifen, MitoTam, can efficiently remove senescent cells due to its inhibition of respiratory complex I and low expression of adenine nucleotide translocase-2 (ANT2) in senescent cells. Therefore, senescent cells can be removed by various strategies, which delays chronic and aging-related diseases and enhances lifespan and healthy conditions in the body.

Prematurely aging mitochondrial DNA mutator mice display subchondral osteopenia and chondrocyte hypertrophy without further osteoarthritis features

Mitochondrial mutations and dysfunction have been demonstrated in several age-related disorders including osteoarthritis, yet its relative contribution to pathogenesis remains unknown. Here we evaluated whether premature aging caused by accumulation of mitochondrial DNA mutations in PolgD275A mice predisposes to the development of knee osteoarthritis. Compared with wild type animals, homozygous PolgD275A mice displayed a specific bone phenotype characterized by osteopenia of epiphyseal trabecular bone and subchondral cortical plate. Trabecular thickness was significantly associated with osteocyte apoptosis rates and osteoclasts numbers were increased in subchondral bone tissues. While chondrocyte apoptosis rates in articular and growth plate cartilage were similar between groups, homozygous mitochondrial DNA mutator mice displayed elevated numbers of hypertrophic chondrocytes in articular calcified cartilage. Low grade cartilage degeneration, predominantly loss of proteoglycans, was present in all genotypes and the development of osteoarthritis features was not found accelerated in premature aging. Somatically acquired mitochondrial DNA mutations predispose to elevated subchondral bone turnover and hypertrophy in calcified cartilage, yet additional mechanical or metabolic stimuli would seem required for induction and accelerated progression of aging-associated osteoarthritis.

Bimodal right ventricular dysfunction after postnatal hyperoxia exposure: implications for the preterm heart.

Rats exposed to postnatal hyperoxia develop right ventricular (RV) dysfunction, mild pulmonary hypertension, and dysregulated cardiac mitochondrial biogenesis when aged to one year, with the degree of cardiac dysfunction and pulmonary hypertension similar to that previously described in young adults born preterm. Here, we sought to understand the impact of postnatal hyperoxia exposure on RV hemodynamic and mitochondrial function across the life span. In Methods, pups from timed-pregnant Sprague-Dawley rats were randomized to normoxia or hyperoxia [fraction of inspired oxygen (), 0.85] exposure for the first 14 days of life, a commonly used model of chronic lung disease of prematurity. RV hemodynamic and mitochondrial function were assessed by invasive measurement of RV pressure-volume loops and by high-resolution respirometry at postnatal day 21 (P21), P90, and P365. In Results, at P21, hyperoxia-exposed rats demonstrated severe pulmonary hypertension and RV dysfunction, accompanied by depressed mitochondrial oxidative capacity. However, significant upregulation of mitochondrial biogenesis at P21 as well as improved afterload led to complete RV hemodynamic and mitochondrial recovery at P90. Mitochondrial DNA mutations were significantly higher by P90 and associated with significant late RV mitochondrial and hemodynamic dysfunction at P365. In conclusion, there appears to be a "honeymoon period" where cardiac hemodynamic and mitochondrial function normalizes following postnatal hyperoxia exposure, only to decline again with ongoing aging. This finding may have significant implications if a long-term pulmonary vascular screening program were to be developed for children or adults with a history of severe prematurity. Further investigation into the mechanisms of recovery are warranted.NEW & NOTEWORTHY Premature birth is associated with increased risk for cardiac dysfunction and failure throughout life. Here, we identify bimodal right ventricular dysfunction after postnatal hyperoxia exposure. Mitochondrial biogenesis serves as an early adaptive feature promoting recovery of cardiac hemodynamic and mitochondrial function. However, the accumulation of mitochondrial DNA mutations results in late mitochondrial and right ventricular dysfunction. This bimodal right ventricular dysfunction may have important implications for the development of screening programs in the preterm population.

Induced in vivo knockdown of the Brca1 gene in skeletal muscle results in skeletal muscle weakness.

Breast cancer 1 early onset gene codes for the DNA repair enzyme, breast cancer type 1 susceptibility protein (BRCA1). The gene is prone to mutations that cause a loss of protein function. BRCA1/Brca1 has recently been found to regulate several cellular pathways beyond DNA repair and is expressed in skeletal muscle. Skeletal muscle specific knockout of Brca1 in mice caused a loss of muscle quality, identifiable by reductions in muscle force production and mitochondrial respiratory capacity. Loss of muscle quality was associated with a shift in muscle phenotype and an accumulation of mitochondrial DNA mutations. These results demonstrate that BRCA1 is necessary for skeletal muscle function and that increased mitochondrial DNA mutations may represent a potential underlying mechanism. Recent evidence suggests that the breast cancer 1 early onset gene (BRCA1) influences numerous peripheral tissues, including skeletal muscle. The present study aimed to determine whether induced-loss of the breast cancer type 1 susceptibility protein (Brca1) alters skeletal muscle function. We induced genetic ablation of exon 11 in the Brca1 gene specifically in the skeletal muscle of adult mice to generate skeletal muscle-specific Brca1 homozygote knockout (Brca1KOsmi ) mice. Brca1KOsmi exhibited kyphosis and decreased maximal isometric force in limb muscles compared to age-matched wild-type mice. Brca1KOsmi skeletal muscle shifted toward an oxidative muscle fibre type and, in parallel, increased myofibre size and reduced capillary numbers. Unexpectedly, myofibre bundle mitochondrial respiration was reduced, whereas contraction-induced lactate production was elevated in Brca1KOsmi muscle. Brca1KOsmi mice accumulated mitochondrial DNA mutations and exhibited an altered mitochondrial morphology characterized by distorted and enlarged mitochondria, and these were more susceptible to swelling. In summary, skeletal muscle-specific loss of Brca1 leads to a myopathy and mitochondriopathy characterized by reductions in skeletal muscle quality and a consequent kyphosis. Given the substantial impact of BRCA1 mutations on cancer development risk in humans, a parallel loss of BRCA1 function in patient skeletal muscle cells would potentially result in implications for human health.

Abstract 431: Mitochondrial-nuclear crosstalk influences accumulation of mitochondrial DNA mutations in mammary tumor progression

Abstract Introduction: Previous studies demonstrated that mitochondrial inheritance may contribute to aggressiveness of metastatic disease. Accumulating evidence suggests the mitochondrial genetic background may influence how certain cancers behave. We utilized Mitochondrial-Nuclear eXchange (MNX) female mice crossed with transgenic mice over-expressing the Her-2 gene and showed mitochondrial DNA (mtDNA)-dependent differences in tumor latency, lung metastasis number and lung metastasis size. We hypothesized that mtDNA mutations accumulate as mammary tumors progress and that the evolution is associated with mtDNA-nuclear DNA cross-talk. To test this hypothesis, we conducted next generation sequencing analyses to examine the spectra of mutations in the mitochondrial genome. Methods: Normal mammary gland, primary tumor and lung metastases [n=5 each] were obtained from FVB/NJ mice with FVB/NJ (designated FF), C57BL/6J (designated FC) or BALB/cJ mtDNA (designated FB). Epithelial cells from mammary gland or tumor cells were carefully isolated by laser capture microdissection in order to minimize contamination from surrounding stromal cell mtDNA. mtDNA was deep sequenced using three pools totaling 182 overlapping primers spanning the whole mitochondrial genome using the Ion TorrentTM PGM System. Sequences were compared to an FVB mtDNA reference sequence to detect variants. Results: Significant differences in the total number of mtDNA mutations were observed between the wild-type and MNX mice. Both FB and FC MNX cohorts exhibited increased mtDNA mutations compared to the wild-type (FF). As tumor progressed, the numbers of and distribution of mutations across the mitochondrial genome increased. ‘Hotspots' were observed in FB mice (S12 rRNA, COX I, ND4, CYTB) that were distinct from common mutations in the FC mice (16S rRNA, COX I). Discussion: As predicted, tumor cells accumulated more mutations in mtDNA as neoplastic cells from the primary tumor progressed to metastasis. Surprisingly, wild-type (FF) mice, even though more clinically aggressive (i.e., more metastases), accumulated fewer mtDNA mutations than tumors arising in the MNX mice. The mutations appear to occur in different sites, depending upon the nuclear-mitochondrial combination. Whether the mtDNA mutations function as contributors to metastatic efficiency has not yet been determined. Nonetheless, the data imply that nuclear-mitochondrial cross-talk influences mtDNA mutational spectra and metastasis and that defining the critical mtDNA genes most commonly involved may eventually be used to predict patient prognosis. Citation Format: Takae M. Brewer, Amanda E. Brinker, Sharon Manley, Carolyn J. Vivian, Danny R. Welch. Mitochondrial-nuclear crosstalk influences accumulation of mitochondrial DNA mutations in mammary tumor progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 431.

Immunolocalisation pattern of complex I–V in ageing human retina: Correlation with mitochondrial ultrastructure

Earlier studies reported accumulation of mitochondrial DNA mutations in ageing and age-related macular degeneration. To know about the mitochondrial status with age, we examined immunoreactivity (IR) to markers of mitochondria (anti-mitochondrial antibody and voltage-dependent anion channel-1) and complex I–V (that mediate oxidative phosphorylation, OXPHOS) in donor human retinas (age: 19–94years; N=26; right eyes). In all samples, at all ages, IR to anti-mitochondrial antibody and voltage-dependent anion channel-1 was prominent in photoreceptor cells. Between second and seventh decade of life, strong IR to complex I–V was present in photoreceptors over macular to peripheral retina. With progressive ageing, the photoreceptors showed a decrease in complex I-IR (subunit NDUFB4) at eighth decade, and a weak or absence of IR in 10 retinas between ninth and tenth decade. Patchy IR to complex III and complex IV was detected at different ages. IR to ND1 (complex I) and complex II and V remained unaltered with ageing. Nitrosative stress (evaluated by IR to a nitro-tyrosine antibody) was found in photoreceptors. Superoxide dismutase-2 was found upregulated in photoreceptors with ageing. Mitochondrial ultrastructure was examined in two young retinas with intact complex IR and six aged retinas whose counterparts showed weak to absence of IR. Observations revealed irregular, photoreceptor inner segment mitochondria in aged maculae and mid-peripheral retina between eighth and ninth decade; many cones possessed autophagosomes with damaged mitochondria, indicating age-related alterations. A trend in age-dependent reduction of complex I-IR was evident in aged photoreceptors, whereas patchy complex IV-IR (subunits I and II) was age-independent, suggesting that the former is prone to damage with ageing perhaps due to oxidative stress. These changes in OXPHOS system may influence the energy budget of human photoreceptors, affecting their viability.

Accumulation of Mitochondrial DNA Mutations Disrupts Cardiac Progenitor Cell Function and Reduces Survival

Transfer of cardiac progenitor cells (CPCs) improves cardiac function in heart failure patients. However, CPC function is reduced with age, limiting their regenerative potential. Aging is associated with numerous changes in cells including accumulation of mitochondrial DNA (mtDNA) mutations, but it is unknown how this impacts CPC function. Here, we demonstrate that acquisition of mtDNA mutations disrupts mitochondrial function, enhances mitophagy, and reduces the replicative and regenerative capacities of the CPCs. We show that activation of differentiation in CPCs is associated with expansion of the mitochondrial network and increased mitochondrial oxidative phosphorylation. Interestingly, mutant CPCs are deficient in mitochondrial respiration and rely on glycolysis for energy. In response to differentiation, these cells fail to activate mitochondrial respiration. This inability to meet the increased energy demand leads to activation of cell death. These findings demonstrate the consequences of accumulating mtDNA mutations and the importance of mtDNA integrity in CPC homeostasis and regenerative potential.

Helicobacter pylori infection and eye diseases: a systematic review.

The connection between Helicobacter pylori (Hp) infection and eye diseases has been increasingly reported in the literature and in active research. The implication of this bacterium in chronic eye diseases, such as blepharitis, glaucoma, central serous chorioretinopathy and others, has been hypothesized. Although the mechanisms by which this association occurs are currently unknown, this review describes shared pathogenetic mechanisms in an attempt to identify a lowest common denominator between eye diseases and Hp infection.The aim of this review is to assess whether different studies could be compared and to establish whether or not Hp infection and Eye diseases share common pathogenetic aspects. In particular, it has been focused on oxidative damage as a possible link between these pathologies.Text word search in Medline from 1998 to July 2014.152 studies were included in our review.Were taken into considerations only studies that related eye diseases more frequent and/or known.Likely oxidative stress plays a key role. All of the diseases studied seem to follow a common pattern that implicates a cellular response correlated with a sublethal dose of oxidative stress. These alterations seem to be shared by both Hp infections and ocular diseases and include the following: decline in mitochondrial function, increases in the rate of reactive oxygen species production, accumulation of mitochondrial DNA mutations, increases in the levels of oxidative damage to DNA, proteins and lipids, and decreases in the capacity to degrade oxidatively damaged proteins and other macromolecules. This cascade of events appears to repeat itself in different diseases, regardless of the identity of the affected tissue. The trabecular meshwork, conjunctiva, and retina can each show how oxidative stress may acts as a common disease effector as the Helicobacter infection spreads, supported by the increased oxidative damage and other inflammation.

Defects in β-cell Ca2+ dynamics in age-induced diabetes.

Little is known about the molecular mechanisms underlying age-dependent deterioration in β-cell function. We now demonstrate that age-dependent impairment in insulin release, and thereby glucose homeostasis, is associated with subtle changes in Ca(2+) dynamics in mouse β-cells. We show that these changes are likely to be accounted for by impaired mitochondrial function and to involve phospholipase C/inositol 1,4,5-trisphosphate-mediated Ca(2+) mobilization from intracellular stores as well as decreased β-cell Ca(2+) influx over the plasma membrane. We use three mouse models, namely, a premature aging phenotype, a mature aging phenotype, and an aging-resistant phenotype. Premature aging is studied in a genetically modified mouse model with an age-dependent accumulation of mitochondrial DNA mutations. Mature aging is studied in the C57BL/6 mouse, whereas the 129 mouse represents a model that is more resistant to age-induced deterioration. Our data suggest that aging is associated with a progressive decline in β-cell mitochondrial function that negatively impacts on the fine tuning of Ca(2+) dynamics. This is conceptually important since it emphasizes that even relatively modest changes in β-cell signal transduction over time lead to compromised insulin release and a diabetic phenotype.

Novel Point Mutations and A8027G Polymorphism in Mitochondrial-DNA-Encoded Cytochrome c Oxidase II Gene in Mexican Patients with Probable Alzheimer Disease

Mitochondrial dysfunction has been thought to contribute to Alzheimer disease (AD) pathogenesis through the accumulation of mitochondrial DNA mutations and net production of reactive oxygen species (ROS). Mitochondrial cytochrome c-oxidase plays a key role in the regulation of aerobic production of energy and is composed of 13 subunits. The 3 largest subunits (I, II, and III) forming the catalytic core are encoded by mitochondrial DNA. The aim of this work was to look for mutations in mitochondrial cytochrome c-oxidase gene II (MTCO II) in blood samples from probable AD Mexican patients. MTCO II gene was sequenced in 33 patients with diagnosis of probable AD. Four patients (12%) harbored the A8027G polymorphism and three of them were early onset (EO) AD cases with familial history of the disease. In addition, other four patients with EOAD had only one of the following point mutations: A8003C, T8082C, C8201T, or G7603A. Neither of the point mutations found in this work has been described previously for AD patients, and the A8027G polymorphism has been described previously; however, it hasn't been related to AD. We will need further investigation to demonstrate the role of the point mutations of mitochondrial DNA in the pathogenesis of AD.

Effects of mitochondrial mutations on hearing and cochlear pathology with age

Age-related hearing loss is a multi-factorial process involving genetic and environmental factors, including exposure to noise and ototoxic agents, as well as pathological processes. Among these is the accumulation of mitochondrial DNA mutations and deletions. The creation of a transgenic mouse with a loss-of-function deletion of the nuclear gene that encodes the polymerase required to repair damaged mitochondrial DNA (PolgA) enabled evaluation of age-related cochlear pathology associated with random mitochondrial DNA deletions that accrue over the lifespan of the mouse.In comparison with their wild-type or heterozygous counterparts, animals with mutated DNA polymerase gamma developed hearing loss most rapidly. Any loss of mitochondrial DNA polymerase function however, resulted in detrimental effects, as evidenced by hearing tests and histological investigation of transgenic heterozygotes. Cochlear pathology in transgenic animals at 10 months of age included loss of neurons and clumping of surviving neurons in the apical turn of the spiral ganglion. Mitochondrial mutations in young animals, on the other hand, were protective against the development of temporary threshold shift in response to relatively low level noise exposure. This supports the idea that temporary threshold shifts are the result of an active process involving mitochondria and respiratory chain activity. Our results indicate that mitochondrial mutation and deletion can certainly contribute to the development of an aging phenotype, specifically age-related hearing loss.

Age-dependent cardiomyopathy in mitochondrial mutator mice is attenuated by overexpression of catalase targeted to mitochondria.

Mitochondrial defects have been found in aging and several age-related diseases. Mice with a homozygous mutation in the exonuclease encoding domain of mitochondrial DNA polymerase gamma (Polg(m/m)) are prone to age-dependent accumulation of mitochondrial DNA mutations and have shown a broad spectrum of aging-like phenotypes. However, the mechanism of cardiac phenotypes in relation to the role of mitochondrial DNA mutations and oxidative stress in this mouse model has not been fully addressed. We demonstrate age-dependent cardiomyopathy in Polg(m/m) mice, which by 13-14 months of age displays marked cardiac hypertrophy and dilatation, impairment of systolic and diastolic function, and increased cardiac fibrosis. This age-dependent cardiomyopathy is associated with increases in mitochondrial DNA (mtDNA) deletions and protein oxidative damage, increased expression of apoptotic and senescence markers, as well as a decline in signaling for mitochondrial biogenesis. The relationship of these changes to mitochondrial reactive oxygen species (ROS) was tested by crossing Polg(m/m) mice with mice that overexpress mitochondrial targeted catalase (mCAT). All of the above phenotypes were partially rescued in Polg(m/m)/mCAT mice. These data indicate that accumulation of mitochondrial DNA damage with age can lead to cardiomyopathy and that this phenotype is partly mediated by mitochondrial oxidative stress.

Mitochondrial abnormalities drive cell death in Wolfram syndrome 2

Mitochondrial abnormalities drive cell death in Wolfram syndrome 2