Mitochondrial transcription factor A regulates mtDNA copy number in mammals

Ekstrand, Mats I.; Falkenberg, Maria; Rantanen, Anja; Park, Chan Bae; Gaspari, Martina; Hultenby, Kjell; Rustin, Pierre; Gustafsson, Claes M.; Larsson, Nils‐Göran

doi:10.1093/hmg/ddh109

Cited by 777 publications

(659 citation statements)

References 38 publications

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“…The expression of mtDNA‐encoded subunits of the respiratory chain is controlled by TFAM 23, 24. TFAM protein abundance was quantified along with NDUFB8 and porin in the same cells.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial DNA Depletion in Respiratory Chain–Deficient Parkinson Disease Neurons

Grünewald

Rygiel

Hepplewhite

et al. 2016

Annals of Neurology

207

162

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ObjectiveTo determine the extent of respiratory chain abnormalities and investigate the contribution of mtDNA to the loss of respiratory chain complexes (CI–IV) in the substantia nigra (SN) of idiopathic Parkinson disease (IPD) patients at the single‐neuron level.MethodsMultiple‐label immunofluorescence was applied to postmortem sections of 10 IPD patients and 10 controls to quantify the abundance of CI–IV subunits (NDUFB8 or NDUFA13, SDHA, UQCRC2, and COXI) and mitochondrial transcription factors (TFAM and TFB2M) relative to mitochondrial mass (porin and GRP75) in dopaminergic neurons. To assess the involvement of mtDNA in respiratory chain deficiency in IPD, SN neurons, isolated with laser‐capture microdissection, were assayed for mtDNA deletions, copy number, and presence of transcription/replication‐associated 7S DNA employing a triplex real‐time polymerase chain reaction (PCR) assay.ResultsWhereas mitochondrial mass was unchanged in single SN neurons from IPD patients, we observed a significant reduction in the abundances of CI and II subunits. At the single‐cell level, CI and II deficiencies were correlated in patients. The CI deficiency concomitantly occurred with low abundances of the mtDNA transcription factors TFAM and TFB2M, which also initiate transcription‐primed mtDNA replication. Consistent with this, real‐time PCR analysis revealed fewer transcription/replication‐associated mtDNA molecules and an overall reduction in mtDNA copy number in patients. This effect was more pronounced in single IPD neurons with severe CI deficiency.InterpretationRespiratory chain dysfunction in IPD neurons not only involves CI, but also extends to CII. These deficiencies are possibly a consequence of the interplay between nDNA and mtDNA‐encoded factors mechanistically connected via TFAM. ANN NEUROL 2016;79:366–378

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“…The expression of mtDNA‐encoded subunits of the respiratory chain is controlled by TFAM 23, 24. TFAM protein abundance was quantified along with NDUFB8 and porin in the same cells.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrial DNA Depletion in Respiratory Chain–Deficient Parkinson Disease Neurons

Grünewald

Rygiel

Hepplewhite

et al. 2016

Annals of Neurology

207

162

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“…In contrast, mtSSB mRNA expression parallels mtDNA abundance in mammalian tissues and is upregulated with mitochondrial biogenesis (Schultz et al., 1998). TFAM and Twinkle are the two main regulators of mtCN, which is directly proportional to expression levels of both proteins (Ekstrand et al., 2004; Tyynismaa et al., 2004). TFAM also stabilizes the nucleoid structure of mtDNA and initiates replication (Kaufman et al., 2007).…”

Section: Discussionmentioning

confidence: 99%

Restoring mitochondrial DNA copy number preserves mitochondrial function and delays vascular aging in mice

et al. 2018

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SummaryAging is the largest risk factor for cardiovascular disease, yet the molecular mechanisms underlying vascular aging remain unclear. Mitochondrial DNA (mtDNA) damage is linked to aging, but whether mtDNA damage or mitochondrial dysfunction is present and directly promotes vascular aging is unknown. Furthermore, mechanistic studies in mice are severely hampered by long study times and lack of sensitive, repeatable and reproducible parameters of arterial aging at standardized early time points. We examined the time course of multiple invasive and noninvasive arterial physiological parameters and structural changes of arterial aging in mice, how aging affects vessel mitochondrial function, and the effects of gain or loss of mitochondrial function on vascular aging. Vascular aging was first detected by 44 weeks (wk) of age, with reduced carotid compliance and distensibility, increased β‐stiffness index and increased aortic pulse wave velocity (PWV). Aortic collagen content and elastin breaks also increased at 44 wk. Arterial mtDNA copy number (mtCN) and the mtCN‐regulatory proteins TFAM, PGC1α and Twinkle were reduced by 44 wk, associated with reduced mitochondrial respiration. Overexpression of the mitochondrial helicase Twinkle (Tw+) increased mtCN and improved mitochondrial respiration in arteries, and delayed physiological and structural aging in all parameters studied. Conversely, mice with defective mitochondrial polymerase‐gamma (PolG) and reduced mtDNA integrity demonstrated accelerated vascular aging. Our study identifies multiple early and reproducible parameters for assessing vascular aging in mice. Arterial mitochondrial respiration reduces markedly with age, and reduced mtDNA integrity and mitochondrial function directly promote vascular aging.

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“…In vitro administration of TFAM reportedly increased mitochondrial respiration rates, biogenesis, and mtDNA levels [89][90][91]. The potential of TFAM as a therapeutic is unlikely owing to its large size and difficulty in BBB penetration [97].…”

Section: Mitochondrial Bioenergetics As a Therapeutic Targetmentioning

confidence: 99%

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

2015

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Alzheimer's disease (AD) has a complex and progressive neurodegenerative phenotype, with hypometabolism and impaired mitochondrial bioenergetics among the earliest pathogenic events. Bioenergetic deficits are well documented in preclinical models of mammalian aging and AD, emerge early in the prodromal phase of AD, and in those at risk for AD. This review discusses the importance of early therapeutic intervention during the prodromal stage that precedes irreversible degeneration in AD. Mechanisms of action for current mitochondrial and bioenergetic therapeutics for AD broadly fall into the following categories: 1) glucose metabolism and substrate supply; 2) mitochondrial enhancers to potentiate energy production; 3) antioxidants to scavenge reactive oxygen species and reduce oxidative damage; 4) candidates that target apoptotic and mitophagy pathways to either remove damaged mitochondria or prevent neuronal death. Thus far, mitochondrial therapeutic strategies have shown promise at the preclinical stage but have had little-to-no success in clinical trials. Lessons learned from preclinical and clinical therapeutic studies are discussed. Understanding the bioenergetic adaptations that occur during aging and AD led us to focus on a systems biology approach that targets the bioenergetic system rather than a single component of this system. Bioenergetic system-level therapeutics personalized to bioenergetic phenotype would target bioenergetic deficits across the prodromal and clinical stages to prevent and delay progression of AD.

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Mitochondrial transcription factor A regulates mtDNA copy number in mammals

Cited by 777 publications

References 38 publications

Mitochondrial DNA Depletion in Respiratory Chain–Deficient Parkinson Disease Neurons

Mitochondrial DNA Depletion in Respiratory Chain–Deficient Parkinson Disease Neurons

Restoring mitochondrial DNA copy number preserves mitochondrial function and delays vascular aging in mice

Targeting the Prodromal Stage of Alzheimer's Disease: Bioenergetic and Mitochondrial Opportunities

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