Most of the genetic information has been lost or transferred to the nucleus during the evolution of mitochondria. Nevertheless, mitochondria have retained their own genome that is essential for ...oxidative phosphorylation (OXPHOS). In mammals, a gene‐dense circular mitochondrial DNA (mtDNA) of about 16.5 kb encodes 13 proteins, which constitute only 1% of the mitochondrial proteome. Mammalian mtDNA is present in thousands of copies per cell and mutations often affect only a fraction of them. Most pathogenic human mtDNA mutations are recessive and only cause OXPHOS defects if present above a certain critical threshold. However, emerging evidence strongly suggests that the proportion of mutated mtDNA copies is not the only determinant of disease but that also the absolute copy number matters. In this review, we critically discuss current knowledge of the role of mtDNA copy number regulation in various types of human diseases, including mitochondrial disorders, neurodegenerative disorders and cancer, and during ageing. We also provide an overview of new exciting therapeutic strategies to directly manipulate mtDNA to restore OXPHOS in mitochondrial diseases.
Mammalian mitochondrial DNA (mtDNA) encodes 13 proteins that are essential for the function of the oxidative phosphorylation system, which is composed of four respiratory-chain complexes and ...adenosine triphosphate (ATP) synthase. Remarkably, the maintenance and expression of mtDNA depend on the mitochondrial import of hundreds of nuclear-encoded proteins that control genome maintenance, replication, transcription, RNA maturation, and mitochondrial translation. The importance of this complex regulatory system is underscored by the identification of numerous mutations of nuclear genes that impair mtDNA maintenance and expression at different levels, causing human mitochondrial diseases with pleiotropic clinical manifestations. The basic scientific understanding of the mechanisms controlling mtDNA function has progressed considerably during the past few years, thanks to advances in biochemistry, genetics, and structural biology. The challenges for the future will be to understand how mtDNA maintenance and expression are regulated and to what extent direct intramitochondrial cross talk between different processes, such as transcription and translation, is important.
The role of mitochondria in aging Bratic, Ana; Larsson, Nils-Göran
The Journal of clinical investigation,
03/2013, Letnik:
123, Številka:
3
Journal Article
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Over the last decade, accumulating evidence has suggested a causative link between mitochondrial dysfunction and major phenotypes associated with aging. Somatic mitochondrial DNA (mtDNA) mutations ...and respiratory chain dysfunction accompany normal aging, but the first direct experimental evidence that increased mtDNA mutation levels contribute to progeroid phenotypes came from the mtDNA mutator mouse. Recent evidence suggests that increases in aging-associated mtDNA mutations are not caused by damage accumulation, but rather are due to clonal expansion of mtDNA replication errors that occur during development. Here we discuss the caveats of the traditional mitochondrial free radical theory of aging and highlight other possible mechanisms, including insulin/IGF-1 signaling (IIS) and the target of rapamycin pathways, that underlie the central role of mitochondria in the aging process.
Respiratory chain dysfunction plays an important role in human disease and aging. It is now well established that the individual respiratory complexes can be organized into supercomplexes, and ...structures for these macromolecular assemblies, determined by electron cryo-microscopy, have been described recently. Nevertheless, the reason why supercomplexes exist remains an enigma. The widely held view that they enhance catalysis by channeling substrates is challenged by both structural and biophysical information. Here, we evaluate and discuss data and hypotheses on the structures, roles, and assembly of respiratory-chain supercomplexes and propose a future research agenda to address unanswered questions.
Milenkovic et al. review the present understanding of the structure, function, and assembly of mitochondrial respiratory chain supercomplexes. Only weak molecular interactions between the individual respiratory chain complexes hold supercomplexes together and their function remains enigmatic because structural data do not support a role in substrate channeling during electron transport.
Dysfunction of the oxidative phosphorylation (OXPHOS) system is a major cause of human disease and the cellular consequences are highly complex. Here, we present comparative analyses of mitochondrial ...proteomes, cellular transcriptomes and targeted metabolomics of five knockout mouse strains deficient in essential factors required for mitochondrial DNA gene expression, leading to OXPHOS dysfunction. Moreover, we describe sequential protein changes during post-natal development and progressive OXPHOS dysfunction in time course analyses in control mice and a middle lifespan knockout, respectively. Very unexpectedly, we identify a new response pathway to OXPHOS dysfunction in which the intra-mitochondrial synthesis of coenzyme Q (ubiquinone, Q) and Q levels are profoundly decreased, pointing towards novel possibilities for therapy. Our extensive omics analyses provide a high-quality resource of altered gene expression patterns under severe OXPHOS deficiency comparing several mouse models, that will deepen our understanding, open avenues for research and provide an important reference for diagnosis and treatment.
Cancer cells depend on mitochondria to sustain their increased metabolic need and mitochondria therefore constitute possible targets for cancer treatment. We recently developed small‐molecule ...inhibitors of mitochondrial transcription (IMTs) that selectively impair mitochondrial gene expression. IMTs have potent antitumor properties in vitro and in vivo, without affecting normal tissues. Because therapy‐induced resistance is a major constraint to successful cancer therapy, we investigated mechanisms conferring resistance to IMTs. We employed a CRISPR‐Cas9 (clustered regularly interspaced short palindromic repeats)‐(CRISP‐associated protein 9) whole‐genome screen to determine pathways conferring resistance to acute IMT1 treatment. Loss of genes belonging to von Hippel–Lindau (VHL) and mammalian target of rapamycin complex 1 (mTORC1) pathways caused resistance to acute IMT1 treatment and the relevance of these pathways was confirmed by chemical modulation. We also generated cells resistant to chronic IMT treatment to understand responses to persistent mitochondrial gene expression impairment. We report that IMT1‐acquired resistance occurs through a compensatory increase of mitochondrial DNA (mtDNA) expression and cellular metabolites. We found that mitochondrial transcription factor A (TFAM) downregulation and inhibition of mitochondrial translation impaired survival of resistant cells. The identified susceptibility and resistance mechanisms to IMTs may be relevant for different types of mitochondria‐targeted therapies.
Synopsis
A CRISPR‐Cas9 screen shows that mTORC1 loss increases OXPHOS and prevents IMT1‐induced cell death whereas loss of VHL confers resistance in an OXPHOS‐independent fashion.
A CRISPR‐Cas9 screen shows that loss of mTORC1 or VHL cause resistance to the inhibition of mtDNA transcription in cancer cells.
Rapamycin promotes survival of IMT1‐treated cancer cells by enhancing mtDNA expression and OXPHOS.
Cells with chronic IMT1 resistance have increased mtDNA levels and OXPHOS capacity.
Decreased mtDNA levels or impaired mitochondrial translation sensitize cancer cells to IMT1 treatment.
A CRISPR‐Cas9 screen shows that mTORC1 loss increases OXPHOS and prevents IMT1‐induced cell death whereas loss of VHL confers resistance in an OXPHOS‐independent fashion.
Mitochondrial dysfunction is heavily implicated in Parkinson disease (PD) as exemplified by the finding of an increased frequency of respiratory chain-deficient dopamine (DA) neurons in affected ...patients. An inherited form of PD is caused by impaired function of Parkin, an E3 ubiquitin ligase reported to translocate to defective mitochondria in vitro to facilitate their clearance. We have developed a reporter mouse to assess mitochondrial morphology in DA neurons in vivo and show here that respiratory chain deficiency leads to fragmentation of the mitochondrial network and to the formation of large cytoplasmic bodies derived from mitochondria. Surprisingly, the dysfunctional mitochondria do not recruit Parkin in vivo, and neither the clearance of defective mitochondria nor the neurodegeneration phenotype is affected by the absence of Parkin. We also show that anterograde axonal transport of mitochondria is impaired in respiratory chain-deficient DA neurons, leading to a decreased supply of mitochondria to the axonal terminals.
The small mammalian mitochondrial DNA (mtDNA) is very gene dense and encodes factors critical for oxidative phosphorylation. Mutations of mtDNA cause a variety of human mitochondrial diseases and are ...also heavily implicated in age-associated disease and aging. There has been considerable progress in our understanding of the role for mtDNA mutations in human pathology during the last two decades, but important mechanisms in mitochondrial genetics remain to be explained at the molecular level. In addition, mounting evidence suggests that most mtDNA mutations may be generated by replication errors and not by accumulated damage.
Mitochondrial dysfunction in adipose tissue occurs in obesity, type 2 diabetes, and some forms of lipodystrophy, but whether this dysfunction contributes to or is the result of these disorders is ...unknown. To investigate the physiological consequences of severe mitochondrial impairment in adipose tissue, we generated mice deficient in mitochondrial transcription factor A (TFAM) in adipocytes by using mice carrying adiponectin‐Cre and TFAM floxed alleles. These adiponectin TFAM‐knockout (adipo‐TFAM‐KO) mice had a 75–81% reduction in TFAM in the subcutaneous and intra‐abdominal white adipose tissue (WAT) and interscapular brown adipose tissue (BAT), causing decreased expression and enzymatic activity of proteins in complexes I, III, and IV of the electron transport chain (ETC). This mitochondrial dysfunction led to adipocyte death and inflammation in WAT and a whitening of BAT. As a result, adipo‐TFAM‐KO mice were resistant to weight gain, but exhibited insulin resistance on both normal chow and high‐fat diets. These lipodystrophic mice also developed hypertension, cardiac hypertrophy, and cardiac dysfunction. Thus, isolated mitochondrial dysfunction in adipose tissue can lead a syndrome of lipodystrophy with metabolic syndrome and cardiovascular complications.—Vernochet, C., Damilano, F., Mourier, A., Bezy, O., Mori, M. A., Smyth, G., Rosenzweig, A., Larsson, N.‐G., Kahn, C. R. Adipose tissue mitochondrial dysfunction triggers a lipodystrophic syndrome with insulin resistance, hepatosteatosis, and cardiovascular complications. FASEB J. 28, 4408–4419 (2014). www.fasebj.org
Mammalian Mitochondria and Aging: An Update Kauppila, Timo E.S.; Kauppila, Johanna H.K.; Larsson, Nils-Göran
Cell metabolism,
01/2017, Letnik:
25, Številka:
1
Journal Article
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Mitochondria were first postulated to contribute to aging more than 40 years ago. During the following decades, multiple lines of evidence in model organisms and humans showed that impaired ...mitochondrial function can contribute to age-associated disease phenotypes and aging. However, in contrast to the original theory favoring oxidative damage as a cause for mtDNA mutations, there are now strong data arguing that most mammalian mtDNA mutations originate as replication errors made by the mtDNA polymerase. Currently, a substantial amount of mitochondrial research is focused on finding ways to either remove or counteract the effects of mtDNA mutations with the hope of extending the human health- and lifespan. This review summarizes the current knowledge regarding the formation of mtDNA mutations and their impact on mitochondrial function. We also critically discuss proposed pathways interlinked with mammalian mtDNA mutations and suggest future research strategies to elucidate the role of mtDNA mutations in aging.
Impaired mitochondrial function can contribute to age-associated diseases and aging. In this review, Kauppila et al. discuss recent data on the origin of mtDNA mutations as replication errors made by the mtDNA polymerase, mitophagy, and potential therapeutic strategies for improving mitochondrial function.
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