ReviewMitochondrial homeostasis: The interplay between mitophagy and mitochondrial biogenesis
Introduction
Mitochondria are double membrane-bound organelles, essential for energy production and cellular homeostasis in eukaryotic cells. Additionally, mitochondria have vital roles in calcium signaling and storage, metabolite synthesis and apoptosis. The strict regulation of mitochondrial mass, distribution and activity is a key aspect of maintenance of cellular homeostasis. The role of mitochondria in animal physiology is extensively investigated and suggests a direct link between mitochondrial metabolism and the process of ageing. Mitochondrial dysfunction is now considered as a major hallmark of ageing, highlighting the significance of proper mitochondrial activity for survival (Lopez-Otin et al., 2013).
Mitochondrial biogenesis and mitochondria-selective autophagy (mitophagy) regulate cellular adaptation in response to mitochondrial malfunction. Thus, mitochondrial biogenesis and elimination of damaged and superfluous mitochondria are highly regulated processes and influence both mitochondrial and cellular homeostasis. The significance of coordination between these processes is underlined by evidence indicating that increased mitochondrial content is a common denominator of several pathologic conditions (Malpass, 2013, Vafai and Mootha, 2012). Similar progressive mitochondrial accumulation is observed during ageing in multiple cell types of diverse organisms ranging from yeast to mammals (Artal-Sanz and Tavernarakis, 2009, Bereiter-Hahn et al., 2008, Kaeberlein, 2010, Lee et al., 2002a, Lee et al., 2002b, Preston et al., 2008). However, the molecular mechanisms that contribute to aberrant increase in mitochondrial mass and disruption of mitochondrial homeostasis remain largely elusive. Here we survey the molecular pathways that govern mitochondrial biogenesis and mitochondrial turnover, and discuss how decoupling of these processes impinges on ageing and age-related diseases.
Section snippets
Molecular pathways regulating mitochondrial biogenesis
Mitochondria are semi-autonomous organelles, possessing their own circular genome. mtDNA encodes 13 proteins with essential function in respiratory complexes, 22 tRNAs and two rRNAs (Calvo and Mootha, 2010). The majority of mitochondrial proteins are encoded by nuclear genes, synthesized within the cytosol and then imported into mitochondria. Mitochondrial biogenesis is a sophisticated and multistep process, including mtDNA transcription and translation, translation of nucleus-derived
Mitochondrial quality control and homeostasis
Alongside their essential metabolic function, mitochondria are also a major source of reactive oxygen species (ROS). Eukaryotes have evolved several quality control mechanisms to preserve mitochondrial homeostasis and prevent cellular damage. Mitochondria contain their own proteolytic system to monitor and degrade misfolded or unfolded proteins inside mitochondrial compartments (Fig. 1A) (Baker and Haynes, 2011, Matsushima and Kaguni, 2012). Furthermore, the proteasome system is involved in the
Co-regulation of mitochondrial biogenesis and mitophagy
The coordination between two opposing processes such as mitochondrial biogenesis and mitophagy fine tunes the quantity and quality of mitochondrial population and allows cells to adjust their mitochondrial content in response to cellular metabolic state, stress and other intracellular or environmental signals. Imbalanced response to either of two processes results in functional deterioration of biological systems and promotes cell death. During ageing and in several pathologic conditions a
Concluding remarks
Mitophagy and mitochondrial biogenesis are tightly coupled. A balanced interplay between these two processes is prerequisite for cellular adaptation and stress resistance. Recent findings hint that imbalance between the two results in cellular degeneration and stimulation of cell death pathways. Although the role of mitochondria-selective autophagy is crucial in many physiological and pathological conditions, the molecular mechanisms regulating mitophagy during ageing are not well defined.
Conflict of interest
The authors have no conflicts of interests.
Acknowledgments
We apologize to those colleagues whose work could not be referenced directly owing to space limitations. Work in the authors' laboratory is also funded by grants from the Greek General Secretariat for Research and Technology, the European Research Council (ERC) and the European Commission 7th Framework Programme.
References (96)
- et al.
Mitochondrial protein quality control during biogenesis and aging
Trends Biochem. Sci.
(2011) - et al.
Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice
Cell Metab.
(2011) - et al.
Yin Yang 1 deficiency in skeletal muscle protects against rapamycin-induced diabetic-like symptoms through activation of insulin/IGF signaling
Cell Metab.
(2012) - et al.
Membrane binding and subcellular targeting of C2 domains
Biochim. Biophys. Acta
(2006) - et al.
Autophagy and mitophagy participate in ocular lens organelle degradation
Exp. Eye Res.
(2013) - et al.
A dual role for Ca(2 +) in autophagy regulation
Cell Calcium
(2011) - et al.
Glucose-induced regulation of protein import receptor Tom22 by cytosolic and mitochondria-bound kinases
Cell Metab.
(2013) - et al.
Microtubule-associated protein 1 light chain 3 (LC3) interacts with Bnip3 protein to selectively remove endoplasmic reticulum and mitochondria via autophagy
J. Biol. Chem.
(2012) - et al.
Stimulation of mitochondrial biogenesis and autophagy by lipopolysaccharide in the neonatal rat cardiomyocyte protects against programmed cell death
J. Mol. Cell. Cardiol.
(2008) - et al.
Regulating mitochondrial outer membrane proteins by ubiquitination and proteasomal degradation
Curr. Opin. Cell Biol.
(2011)
Role of PINK1 binding to the TOM complex and alternate intracellular membranes in recruitment and activation of the E3 ligase Parkin
Dev. Cell
The hallmarks of aging
Cell
Pivotal role of the C2 domain of the Smurf1 ubiquitin ligase in substrate selection
J. Biol. Chem.
Matrix proteases in mitochondrial DNA function
Biochim. Biophys. Acta
Cargo-selected transport from the mitochondria to peroxisomes is mediated by vesicular carriers
Curr. Biol.
Mitophagy: mitofusin recruits a mitochondrial killer
Curr. Biol.
Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy
Cell
Aging-induced alterations in gene transcripts and functional activity of mitochondrial oxidative phosphorylation complexes in the heart
Mech. Ageing Dev.
Mitochondrial protein quality control by the proteasome involves ubiquitination and the protease Omi
J. Biol. Chem.
PGC-1alpha over-expression promotes recovery from mitochondrial dysfunction and cell injury
Biochem. Biophys. Res. Commun.
The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity
J. Biol. Chem.
Regulation of mitochondrial protein import by cytosolic kinases
Cell
PARIS (ZNF746) repression of PGC-1alpha contributes to neurodegeneration in Parkinson's disease
Cell
A vesicular transport pathway shuttles cargo from mitochondria to lysosomes
Curr. Biol.
In vivo correction of COX deficiency by activation of the AMPK/PGC-1alpha axis
Cell Metab.
Oxidative stress induces protein kinase D activation in intact cells. Involvement of Src and dependence on protein kinase C
J. Biol. Chem.
PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility
Cell
Calcium induces increases in peroxisome proliferator-activated receptor gamma coactivator-1alpha and mitochondrial biogenesis by a pathway leading to p38 mitogen-activated protein kinase activation
J. Biol. Chem.
Enhanced autophagy plays a cardinal role in mitochondrial dysfunction in type 2 diabetic Goto-Kakizaki (GK) rats: ameliorating effects of (−)-epigallocatechin-3-gallate
J. Nutr. Biochem.
Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane
J. Biol. Chem.
Regulation of autophagy by extracellular signal-regulated protein kinases during 1-methyl-4-phenylpyridinium-induced cell death
Am. J. Pathol.
Postfertilization autophagy of sperm organelles prevents paternal mitochondrial DNA transmission
Science
Prohibitin couples diapause signalling to mitochondrial metabolism during ageing in C. elegans
Nature
IKKalpha and alternative NF-kappaB regulate PGC-1beta to promote oxidative muscle metabolism
J. Cell Biol.
Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains
Mol. Cell Biol.
Structural implications of mitochondrial dynamics
Biotechnol. J.
The Parkinson's disease-linked proteins Fbxo7 and Parkin interact to mediate mitophagy
Nat. Neurosci.
The mitochondrial proteome and human disease
Annu. Rev. Genomics Hum. Genet.
AMPK regulates energy expenditure by modulating NAD + metabolism and SIRT1 activity
Nature
Mitochondrial Ca(2 +) signals in autophagy
Cell Calcium
Cyclophilin D is required for mitochondrial removal by autophagy in cardiac cells
Autophagy
Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy
Hum. Mol. Genet.
PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria
Science
Mutant LRRK2 elicits calcium imbalance and depletion of dendritic mitochondria in neurons
Am. J. Pathol.
mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex
Nature
Mitochondrially localized ERK2 regulates mitophagy and autophagic cell stress: implications for Parkinson's disease
Autophagy
Mitochondrial biogenesis through activation of nuclear signaling proteins
Cold Spring Harb. Perspect. Biol.
Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy
Science
Cited by (331)
Senolytic therapeutics: An emerging treatment modality for osteoarthritis
2024, Ageing Research ReviewsThe opposite role of lactate dehydrogenase a (LDHA) in cervical cancer under energy stress conditions
2024, Free Radical Biology and MedicineDocosahexaenoic acid (DHA) inhibits abdominal fat accumulation by promoting adipocyte apoptosis through PPARγ-LC3-BNIP3 pathway-mediated mitophagy
2024, Biochimica et Biophysica Acta - Molecular and Cell Biology of LipidsEstrogen receptor β exerts neuroprotective effects by fine-tuning mitochondrial homeostasis through NRF1/PGC-1α
2023, Neurochemistry International