Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans

Palikaras, Konstantinos; Lionaki, Eirini; Tavernarakis, Nektarios

doi:10.1038/nature14300

Cited by 594 publications

(633 citation statements)

References 39 publications

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“…Under physiologic conditions in the presence of parkin, there is likely a homeostatic mechanisms that regulates the level of mitochondrial numbers in response to the needs of the cell in a balanced pathway of degradation (mitophagy) and production (biogenesis) of mitochondria that is regulated by parkin, with PARIS playing a central role in the biogenesis arm. Consistent with the notion of a homeostatic mechanism is the recent report of the coordination of mitophagy and mitochondrial biogenesis during aging in Caenorhabditis elegans (32). Further studies are required to investigate this possibility.…”

Section: Discussionsupporting

confidence: 55%

Parkin loss leads to PARIS-dependent declines in mitochondrial mass and respiration

Stevens

Kang

Lee

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

201

185

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Mutations in parkin lead to early-onset autosomal recessive Parkinson's disease (PD) and inactivation of parkin is thought to contribute to sporadic PD. Adult knockout of parkin in the ventral midbrain of mice leads to an age-dependent loss of dopamine neurons that is dependent on the accumulation of parkin interacting substrate (PARIS), zinc finger protein 746 (ZNF746), and its transcriptional repression of PGC-1α. Here we show that adult knockout of parkin in mouse ventral midbrain leads to decreases in mitochondrial size, number, and protein markers consistent with a defect in mitochondrial biogenesis. This decrease in mitochondrial mass is prevented by short hairpin RNA knockdown of PARIS. PARIS overexpression in mouse ventral midbrain leads to decreases in mitochondrial number and protein markers and PGC-1α-dependent deficits in mitochondrial respiration. Taken together, these results suggest that parkin loss impairs mitochondrial biogenesis, leading to declining function of the mitochondrial pool and cell death. Recently, the parkin interacting substrate (PARIS) also known as zinc finger protein 746 (ZNF746) was shown to be required for loss of DA neurons in adult conditional parkin knockout (KO) mice (19). PARIS is polyubiquitinated by parkin via lysine-48 targeting it for ubiquitin proteasomal degradation. Deletion of parkin in adult mice leads to an age-dependent progressive loss of DA neurons that is due to the accumulation of PARIS because depletion of PARIS in adult conditional parkin knockout mice prevents the loss of DA neurons (19). PARIS is a transcriptional repressor that regulates the expression of peroxisome proliferator-activated receptor gamma, coactivator 1α (PGC-1α), a master coregulator of mitochondrial function, biogenesis, and mitochondrial oxidative stress management (19,20). In adult conditional parkin knockout mice, there is a reduction in PGC-1α levels that is dependent on PARIS because reduction in PARIS reverses the reduction in PGC-1α levels (19). PARIS overexpression, at levels equivalent to those in the adult conditional parkin knockout mice, also leads to defects in PGC-1α and causes the selective loss of DA neurons (19). PGC-1α overexpression prevents the defects in PGC-1α signaling and the loss of DA neurons, suggesting that PARIS kills DA neurons in a PGC-1α-dependent fashion (19).Because PGC-1α is a master coregulator of mitochondrial function and mitochondrial defects are a consistent feature of PD, mitochondria were assessed in the adult conditional parkin knockout mice. Here we show that adult conditional knockout of parkin leads to reductions in mitochondrial mass that are dependent upon PARIS. Moreover, PARIS accumulation leads to substantial deficits in mitochondrial respiration that are PGC-1α dependent. Our findings are consistent with parkin regulation of mitochondrial biogenesis. ResultsReduced Mitochondrial Size and Number in Adult Conditional Parkin Knockouts. Adult conditional parkin knockout mice were generated as previously described by injecting a lentiviru...

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Section: Discussionsupporting

confidence: 55%

Parkin loss leads to PARIS-dependent declines in mitochondrial mass and respiration

Stevens

Kang

Lee

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

201

185

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“…To achieve this, we silenced by RNAi dct-1 , an evolutionarily conserved regulator of mitophagy 33 . dct-1 RNAi reduced GMC101’s health- and life-span already in basal conditions (Extended Data Fig.…”

Section: Reducing Mitochondrial Translation Lowers Aβ Proteotoxicitymentioning

confidence: 99%

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

Sorrentino

Romani

Mouchiroud

et al. 2017

Nature

481

397

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Alzheimer’s disease (AD) is a common and devastating disease characterized by the aggregation of amyloid-β peptide (Aβ), yet we know relatively little about the underlying molecular mechanisms or how to treat AD patients. Here, we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in Aβ proteotoxic diseases in human, mouse and C. elegans, and which involves the UPRmt and mitophagy pathways. Using the worm model of Aβ proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed the induction of this mitochondrial stress response as key to maintain mitochondrial proteostasis and health. Importantly, boosting mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms, and in AD transgenic mice. Our data support the relevance of enhancing mitochondrial proteostasis to delay Aβ proteotoxic diseases, such as AD.

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“…[3][4][5][6] The reason underlying this phenomenon remained elusive. We found that age-related mitophagy decline causes progressive accumulation of mitochondria in the nematode Caenorhabditis elegans.…”

mentioning

confidence: 99%

“…In addition to its pro-longevity effects, mitophagy confers resistance to various stressors, including starvation, genotoxic, mitochondrial and oxidative stress. 3 Maintenance of mitochondrial homeostasis requires both clearance of damaged and generation of fresh, functional mitochondria. Emerging evidence indicates that coordination between mitochondrial biogenesis and mitophagy is essential for proper mitochondrial homeostasis.…”

mentioning

confidence: 99%

Balancing mitochondrial biogenesis and mitophagy to maintain energy metabolism homeostasis

2015

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Mitochondria, the main energy hub of the cell, are highly dynamic organelles, playing essential roles in fundamental cellular processes. Mitochondrial function impinges on several signalling pathways modulating cellular metabolism, cell survival and healthspan. Accordingly, impairment of mitochondria has been associated with numerous pathological conditions and ageing. Maintenance of cellular and organismal homeostasis thus hinges on fine-tuning mitochondrial quality control. Mitochondrial biogenesis and mitochondrial selective autophagy (mitophagy), two opposing cellular pathways, coordinately regulate mitochondrial content to sustain energy metabolism, in response to cellular metabolic state, stress and other intracellular or environmental signals. It is not surprising, therefore, that disequilibrium or imbalance between mitochondrial proliferation and degradation processes underlies the onset and progressive unfolding of several pathological conditions in humans, including neurodegenerative diseases, myopathies and other age-associated disorders.Mitochondrial biogenesis is a complex and multistep cellular process, which involves mtDNA transcription and translation, translation of transcripts derived from nucleus, recruitment of newly synthesized proteins and lipids, import and assembly of mitochondrial and nuclear products in the expanding mitochondrial network. Spatiotemporal control of mitochondrial biogenesis is mediated by numerous transcription factors in response to diverse stimuli, including both intracellular signals and environmental stimuli (nutrient availability, growth factors and hormones, toxins, temperature and oxygen fluctuations, among others). The master regulator of mitochondrial energy metabolism is the peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), the best-studied member of the peroxisome proliferator activated receptor family of transcription co-activators, which orchestrates the activity of several transcription factors involved in mitochondrial biogenesis and function. 1 These include the nuclear respiratory factors (NRF1 and NRF2), the estrogen-related receptors (ERR-α, -β and -γ) and the nuclear factor erythroid 2-related factor 2 (NRF2/NFE2L2) that are part of a complex transcriptional network that regulates mitochondrial biogenesis and energy metabolism. 1,2 Alongside their essential roles in cell and animal physiology, mitochondria are also the major source of potentially hazardous reactive oxygen species as by-products of respiration. Thus, eukaryotic cells have evolved a wide arsenal of quality control mechanisms to preserve mitochondrial homeostasis and prevent cellular damage and eventual death. Mitophagy, a selective type of autophagy, is triggered upon accumulation of damaged or superfluous mitochondria. Dysfunctional mitochondria are targeted and engulfed by double-membrane vesicles known as autophagosomes and are transferred for degradation in lysosomes. Cells induce mitophagy to regulate the size and quality of their mitochondrial network...

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Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans

Cited by 594 publications

References 39 publications

Parkin loss leads to PARIS-dependent declines in mitochondrial mass and respiration

Parkin loss leads to PARIS-dependent declines in mitochondrial mass and respiration

Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity

Balancing mitochondrial biogenesis and mitophagy to maintain energy metabolism homeostasis

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