Mitochondrial biogenesis and clearance: a balancing act

Abstract

Mitochondria are semi-autonomous organelles of prokaryotic origin that are postulated to have been acquired by eukaryotic cells through an early endosymbiotic event. Except for their main role in energy production, they are also implicated in fundamental cellular processes, including ion homeostasis, lipid metabolism, and initiation of apoptotic cell death. Perturbed mitochondrial function has been correlated with severe human pathologies such as type-2 diabetes, cardiovascular, and neurodegenerative diseases. Thus, proper mitochondrial physiology is a prerequisite for health and survival. Cells have developed sophisticated and elaborate mechanisms to adapt to stress conditions and alterations in metabolic demands, by regulating mitochondrial number and function. Hence, the generation of new and the removal of damaged or unwanted mitochondria are highly regulated processes that need to be accurately coordinated for the maintenance of mitochondrial and cellular homeostasis. Here, we survey recent research findings that advance our understanding and highlight the importance of the underlying molecular mechanisms. Abbreviations AGO2, argonaute 2; AMPK, AMP-activated protein kinase; ATFS1, activating transcription factor associated with stress 1; Atg32, autophagyrelated 32; Bcl-2, B-cell lymphoma 2; BCL2L13, Bcl-2-like 13; Bnip3, Bcl-2/adenovirus E1B 19kDa-interacting protein 3; Bnip3L/Nix, Bnip3-like/NIP3-like protein X; CCCP, carbonyl cyanide m-chlorophenyl hydrazone; CerS1, ceramide synthase 1; CL, cardiolipin; COXIV, cytochorome C oxidase subunit IV; CREB, cAMP response element-binding protein; DAF-16, abnormal DAuer Formation 16; DCT-1, DAF-16/ FOXO controlled germline tumor-affecting 1; DRP1, dynamin-related protein; ER, endoplasmic reticulum; ERRα, estrogen-related receptor alpha; FOXO, forkhead box O; FUNDC1, FUN14 domain-containing 1; GABARAP, GABA(A) receptor-associated protein; GABP, GA-binding protein transcription factor; GCN5L1, general control of amino acid synthesis 6-like 1; HO-1, heme oxygenase-1; ILS, insulin-like signaling; IMM, inner mitochondrial membrane; IMS, intermembrane space; KEAP1, Kelch-Like ECH-associated protein 1; LC3-II, lipidated form of LC3; LC3, light chain 3; LIR, LC3-interacting region; MAPK, mitogen-activated protein kinase; Mba1, multi-copy Bypass of AFG3; MDVs, mitochondrial-derived vesicles; MFN2, mitofusin 2; miRNA, micro RNA; MPP, mitochondrial processing peptidase; MtCK, mitochondrial creatine kinase; mtDNA, mitochondrial DNA; MTHFD2, methylenetetrahydrofolate dehydrogenase (NADP + dependent) 2; mTOR, mechanistic target of rapamycin; NAC, nascent polypeptide-associated complex; NBR1, neighbor of BRCA 1 gene 1; NDP52, nuclear dot protein 52 kDa; NDPK-D, nucleoside diphosphatate kinase-D; NFE2L, nuclear factor erythroid 2-like; NRF, nuclear respiratory factor; OMM, outer mitochondrial membrane; OPA1, optic atrophy 1; p62, nucleoporin 62; PARIS, Parkin-interacting substrate; PARL, presenilin-associated rhomboid-like protease; PGAM-5, phosphoglycerate mutase homolog-5; PGC1α...

Mitochondrial fusion, fission, and mitochondrial toxicity

“…Just as fusion and fission dynamically regulate mitochondrial morphology, mitochondrial production (mitobiogenesis) and removal dynamically regulate mitochondrial quantity and quality (Ploumi et al 2017). Mitobiogenesis is a regulated process permitting a coordinated, increased production of nuclear and mitochondrial-encoded proteins, mtDNA (addressed in detail by Chan (this issue), and other components (reviewed in (Dominy and Puigserver 2013)).…”

“…Regulation of mitobiogenesis varies among tissues, but often involves the peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR) kinase, sirtuins (e.g. SIRT1), nuclear respiratory factors (NRF1 and NRF2), nuclear factor-erythroid 2-like 2 (NFE2L2; also referred to as Nrf2), and estrogen-related receptors (ERR-α, ERR-β, ERR-γ) (Ploumi et al 2017). In the context of stressors, mitobiogenesis may be upregulated either to increase mitochondrial function in general, or to compensate for increased rates of removal of damaged mitochondria (Dorn et al 2015).…”

“…This process is mediated in part by PTEN-induced putative kinase 1 (PINK1), a mitochondrial kinase that accumulates on dysfunctional mitochondria and recruits and activates proteins including Parkin (PARK2), a ubiquitin ligase; both are involved in some forms of mitophagy as well as micro-mitophagy (Lemasters 2014; Narendra et al 2012; Palikaras and Tavernarakis 2014). In addition to PINK1 and Parkin, a large and increasing number of other proteins are being identified as capable of participating in mitophagy (Ploumi et al 2017; Wei et al 2017). Many forms of mitochondrial degradation are inducible by stimuli including nutrient or caloric deprivation and loss of membrane potential.…”

“…Perhaps unsurprisingly, regulation of mitobiogenesis and mitophagy is frequently coordinated, often by the same transcription factors, thus permitting increased turnover without a decrease in mass under stressed conditions; an imbalance in these processes underlies some disease states (Ploumi et al 2017). In most cases, initiation of mitophagy is somewhat slower than fusion and fission, occurring over minutes to hours, although some forms of mitophagy are faster than others (Lemasters 2014).…”

Abrogating Mitochondrial Dynamics in Mouse Hearts Accelerates Mitochondrial Senescence

“…Conceptually, mitochondrial abundance can be adjusted through regulated organelle production or elimination, while the fitness of mitochondrial populations is maintained by selectively purging damaged mitochondria and replacing them with newly generated healthy organelles. Thus, mitochondrial introduction through biogenesis and removal through mitophagy are homeostatically coordinated (Ploumi et al, 2016). A recent study of C. elegans identified signaling events essential to age-related engagement of mitophagy and biogenesis, without which cellular functioning was compromised and premature senescence occurred (Palikaras et al, 2015).…”