Mitophagy is an evolutionarily conserved cellular process to remove dysfunctional or superfluous mitochondria, thus fine-tuning mitochondrial number and preserving energy metabolism. In this Review, we survey recent advances towards elucidating the molecular mechanisms that mediate mitochondrial elimination and the signalling pathways that govern mitophagy. We consider the contributions of mitophagy in physiological and pathological contexts and discuss emerging findings, highlighting the potential value of mitophagy modulation in therapeutic intervention.

Impaired mitochondrial maintenance in disparate cell types is a shared hallmark of many human pathologies and ageing. How mitochondrial biogenesis coordinates with the removal of damaged or superfluous mitochondria to maintain cellular homeostasis is not well understood. Here we show that mitophagy, a selective type of autophagy targeting mitochondria for degradation, interfaces with mitochondrial biogenesis to regulate mitochondrial content and longevity in Caenorhabditis elegans. We find that DCT-1 is a key mediator of mitophagy and longevity assurance under conditions of stress in C. elegans. Impairment of mitophagy compromises stress resistance and triggers mitochondrial retrograde signalling through the SKN-1 transcription factor that regulates both mitochondrial biogenesis genes and mitophagy by enhancing DCT-1 expression. Our findings reveal a homeostatic feedback loop that integrates metabolic signals to coordinate the biogenesis and turnover of mitochondria. Uncoupling of these two processes during ageing contributes to overproliferation of damaged mitochondria and decline of cellular function.

Oxidative protein folding in the mitochondrial intermembrane space requires the transfer of a disulfide bond from MIA40 to the substrate. During this process MIA40 is reduced and regenerated to a functional state through the interaction with the flavin-dependent sulfhydryl oxidase ALR. Here we present the mechanistic basis of ALR-MIA40 interaction at atomic resolution by biochemical and structural analyses of the mitochondrial ALR isoform and its covalent mixed disulfide intermediate with MIA40. This ALR isoform contains a folded FAD-binding domain at the C-terminus and an unstructured, flexible N-terminal domain, weakly and transiently interacting one with the other. A specific region of the N-terminal domain guides the interaction with the MIA40 substrate binding cleft (mimicking the interaction of the substrate itself), without being involved in the import of ALR. The hydrophobicity-driven binding of this region ensures precise protein-protein recognition needed for an efficient electron transfer process.

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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Mitochondria represent the major bioenergetic hub coordinating cellular and organismal homeostasis. The underlying causes of many pathologies tormenting humans converge on impaired mitochondrial maintenance. Mitochondria-specific autophagy (mitophagy), a cellular catabolic process targeting mitochondria, holds a prominent role in mitochondrial quality control. In addition to core autophagic machinery components, mitophagy exploits a variety of molecules that identify damaged or superfluous mitochondria and mediate their elimination. Signaling pathways integrating environmental and genetic stimuli interact with key mitophagy effectors to activate cellular stress response mechanisms, ultimately modulating health and lifespan. Here, we review the signaling cascades and molecular mechanisms that govern the process of mitophagy and discuss their involvement in ageing and neurodegeneration. This article is part of a Special Issue entitled: Mitochondrial Dysfunction in Aging.

Lionaki, E., Aivaliotis, M., Pozidis, C., and Tokatlidis, K. (2010) The Nterminal shuttle domain of Erv1 determines the affinity for Mia40 and mediates electron transfer to the catalytic Erv1 core in yeast mitochondria. Antioxidants and Redox Signaling, 13 (9 AbstractErv1 and Mia40 constitute the two important components of the disulfide relay system that mediates oxidative protein folding in the mitochondrial intermembrane space. Mia40 is the import receptor that recognizes the substrates introducing disulfide bonds while it is reduced. A key function of Erv1 is to recycle Mia40 to its active oxidative state. Our aims here were to dissect the domain of Erv1 that mediates the protein-protein interaction with Mia40 and to investigate the interactions between the shuttle domain of Erv1 and its catalytic core and their relevance for the interaction with Mia40. We purified these domains separately as well as cysteine mutants in the shuttle and the active core domains. The noncovalent interaction of Mia40 with Erv1 was measured by isothermal titration calorimetry, whereas their covalent mixed disulfide intermediate was analyzed in reconstitution experiments in vitro and in organello. We established that the N-terminal shuttle domain of Erv1 is necessary and sufficient for interaction to occur. Furthermore, we provide direct evidence for the intramolecular electron transfer from the shuttle cysteine pair of Erv1 to the core domain. Finally, we reconstituted the system by adding in trans the N-and C-terminal domains of Erv1 together with its substrate Mia40. Antioxid. Redox Signal. 13, 1327-1339.

a b s t r a c tAgeing in diverse species ranging from yeast to humans is associated with the gradual, lifelong accumulation of molecular and cellular damage. Autophagy, a conserved lysosomal, self-destructive process involved in protein and organelle degradation, plays an essential role in both cellular and whole-animal homeostasis. Accumulating evidence now indicates that autophagic degradation declines with age and this gradual reduction of autophagy might have a causative role in the functional deterioration of biological systems during ageing. Indeed, loss of autophagy gene function significantly influences longevity. Moreover, genetic or pharmacological manipulations that extend lifespan in model organisms often activate autophagy. Interestingly, conserved signalling pathways and environmental factors that regulate ageing, such as the insulin/IGF-1 signalling pathway and oxidative stress response pathways converge on autophagy. In this article, we survey recent findings in invertebrates that contribute to advance our understanding of the molecular links between autophagy and the regulation of ageing. In addition, we consider related mechanisms in other organisms and discuss their similarities and idiosyncratic features in a comparative manner.