Redox homeostasis, oxidative stress and mitophagy

Abstract

Autophagy is a ubiquitous homeostatic mechanism for the degradation or turnover of cellular components. Degradation of mitochondria via autophagy (mitophagy) is involved in a number of physiological processes including cellular homeostasis, differentiation and aging. Upon stress or injury, mitophagy prevents the accumulation of damaged mitochondria and the increased steady state levels of reactive oxygen species leading to oxidative stress and cell death. A number of human diseases, particularly neurodegenerative disorders, have been linked to the dysregulation of mitophagy. In this mini-review, we aimed to review the molecular mechanisms involved in the regulation of mitophagy and their relationship with redox signaling and oxidative stress.

Keywords: Autophagy; Fission; Fusion; Mitochondrial dynamics.

Figure 1.. Autophagy.

Autophagy requires the formation of distinct complexes during four sequential stages: (1) Induction and (2) Nucleation of the phagophore; (3) Elongation and closure of the autophagosomes; and (4) Fusion between autophagosomes and lysosomes. (1) The mechanistic target of rapamycin complex 1 (mTORC1) is regulated by stimulation of the class I phosphoinositide 3-kinase (PI3K)–protein kinase B (AKT) pathway by growth factors, and via the regulation of Rag guanosine triphosphatases (GTPases) and the adenosine monophosphate (AMP)-activated protein kinase (AMPK) by amino acid and energy depletion, respectively. mTORC1 negatively regulates the unc-51-like kinase-1 (ULK1) and class III PI3K complex I (PIK3C3-CI). Starvation or growth factor withdrawal inhibit mTORC1, leading to the dephosphorylation / activation of ULK1. (2) ULK1 activation phosphorylates and activates the PIK3C3-CI that in turn generates phosphatidylinositol-3-phosphate (PIP₃), which recruit the autophagy-related protein (Atg) 5-Atg12 and Atg8 / microtubule-associated light chain 3 (LC3) conjugation systems. (3) LC3 lipidation to LC3-II is used as a platform for the recognition of cellular targets, including mitochondria via specific receptors. (4) Subsequently, autophagosomes move across microtubules to encounter lysosomes. Autophagosome-lysosome fusion (autolysosome) is the final step where lysosomal hydrolases are released for the degradation of autophagosome cargo. P, highlights phosphorylation events; Ox, highlights sites for redox regulation of autophagy. Ambra1, autophagy and beclin 1 regulator 1; Beclin 1, B-cell lymphoma 2-interacting myosin/moesin-like coiled-coil protein 1; NRBF2, nuclear receptor binding factor 2; NOX, nicotinamide adenine dinucleotide phosphate oxidase; PDK1, phosphoinositide-dependent kinase 1; PIP₂, phosphatidylinositol 4,5-bisphosphate; PTEN, phosphatase and tensin homolog; PTP1B, protein tyrosine phosphatase 1B; RB1CC1, retinoblastoma-associated protein-inducible coiled-coil protein 1; Rheb, Ras homolog enriched in brain; RTK, receptor tyrosine kinase; SNAREs, soluble N-ethylmaleimide-sensitive factor attachment protein receptors; TSC1/2, tuberous sclerosis complex proteins 1 and 2; Vps15; vacuolar protein sorting 15.

Figure 2.. Mitochondrial fusion, fission and mitophagy.

Mitochondrial maintenance is a dynamic process undergoing continuous events of fission and fusion to preserve proper mitochondrial functions. (1) Fission requires local organization of the mitochondrial fission 1 protein (Fis1) and recruitment of the dynamin-related protein 1 (Drp1) guanosine triphosphatase (GTPase) for assembly of the fission machinery that subsequently leads to membrane scission. (2) Fusion is mediated by dynamin GTPases mitofusins 1 (Mfn1) and 2 at the outer membrane and optic atrophy protein (Opa1) at the inner membrane that tether adjacent mitochondria together. Mitochondrial fission precedes mitophagy, in order to transform elongated mitochondria into a form suitable for engulfment, or upon oxidative stress, to mediate the degradation of damaged mitochondria decreasing mitochondria-derived ROS formation. (3) Loss of mitochondrial membrane potential (ΔΨm) leads to the translocation of the phosphatase and tensin homologue (PTEN)-induced putative kinase 1 (PINK1) and the E3-ubiquitin (Ub) ligase Parkin (PARK2) to the mitochondria, where it promotes the ubiquitination of proteins in the mitochondrial membrane, which recruit the autophagy receptors (p62, optineurin [OPTN] and the nuclear dot protein 52 [NDP52]) that target these mitochondria for removal (4). (5) Ubiquitin-independent mitophagy is involved primarily in metabolic reprogramming during differentiation and cancer, as well as during mitochondria turnover in response to hypoxia, and is mediated by several mitophagy receptors including NIP3-like protein X (Nix), Bcl-2 interacting protein 3 (Bnip3) and FUN14 domain containing 1 (FUNDC1) protein. (6) Transport of mitochondria to axonal and dendritic terminations is essential to meet energy demands associated with synaptic transmission. PINK1 and Parkin mediate phosphorylation, ubiquitination and degradation of the mitochondrial Rho–GTPase (Miro) leading to the detachment of mitochondria from microtubules. (7) Oxidized glutathione (GSSG) accumulation has been demonstrated to mediate the oxidation of Mfn’s cysteines (Cys) by disulphide bond formation (-S-S-), causing a conformational change that aid in tethering of Mfns to enhance membrane fusion. P, highlights phosphorylation events; Ox, highlights sites for redox regulation of mitophagy. AMPK, adenosine monophosphate (AMP)-activated protein kinase; HIF1α, hypoxia-inducible factor-1α, Keap1, kelch Like ECH Associated Protein 1; KIF5a, Kinesin Family Member 5A; ULK1, unc-51-like kinase-1.