Mitochondrial quality control and communications with the nucleus are important in maintaining mitochondrial function and cell health

Abstract

Background: The maintenance of cell metabolism and homeostasis is a fundamental characteristic of living organisms. In eukaryotes, mitochondria are the cornerstone of these life supporting processes, playing leading roles in a host of core cellular functions, including energy transduction, metabolic and calcium signalling, and supporting roles in a number of biosynthetic pathways. The possession of a discrete mitochondrial genome dictates that the maintenance of mitochondrial 'fitness' requires quality control mechanisms which involve close communication with the nucleus.

Scope of review: This review explores the synergistic mechanisms that control mitochondrial quality and function and ensure cellular bioenergetic homeostasis. These include antioxidant defence mechanisms that protect against oxidative damage caused by reactive oxygen species, while regulating signals transduced through such free radicals. Protein homeostasis controls import, folding, and degradation of proteins underpinned by mechanisms that regulate bioenergetic capacity through the mitochondrial unfolded protein response. Autophagic machinery is recruited for mitochondrial turnover through the process of mitophagy. Mitochondria also communicate with the nucleus to exact specific transcriptional responses through retrograde signalling pathways.

Major conclusions: The outcome of mitochondrial quality control is not only reliant on the efficient operation of the core homeostatic mechanisms but also in the effective interaction of mitochondria with other cellular components, namely the nucleus.

General significance: Understanding mitochondrial quality control and the interactions between the organelle and the nucleus will be crucial in developing therapies for the plethora of diseases in which the pathophysiology is determined by mitochondrial dysfunction. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.

Keywords: Antioxidant defence; Mitochondria; Mitophagy; Protein homeostasis; Quality control; Retrograde signalling.

Fig. 1

The path of ROS. Superoxide radicals (^•O₂) are typically converted to hydrogen peroxide (H₂O₂) by mitochondrial manganese superoxide dismutase (MnSOD). H₂O₂ can readily diffuse through lipid membranes and react with a multitude of antioxidant components. At low concentrations H₂O₂ is most frequently converted to H₂O through the activity of peroxiredoxins (Prx-O: oxidised; Prx-R: reduced), but at higher concentrations glutathione peroxidases (GPx-O: oxidised; GPx-R: reduced) can provide additional support in facilitating this conversion in order to deal with oxidative stress. Once oxidised by H₂O₂, both Prx and GPx can transfer their redox state to thioredoxins (Trx-O: oxidised; Trx-R: reduced) and glutathione (GSSG: oxidised; GSH: reduced) respectively and are thus recycled back to a reduced state. Reduction of Trx and GSH is catalysed by thioredoxin reductase (TR2) and glutathione reductase (GR) respectively. Catalase converts H₂O₂ to H₂O but due to its peroxisomal location is typically functional only under increased oxidative stress conditions. When there is a build of ^•O₂⁻ and H₂O₂ these can react with iron (Fe) according to Fenton chemistry, and generate the highly reactive and damaging hydroxyl radical (^•OH⁻). If ^•O₂⁻ is not dealt with sufficiently by MnSOD it can react with ^•NO and generate the peroxynitrite radical (^•ONOO).

Fig. 2

Factors involved in mitochondrial retrograde signalling and UPR^mt. Mitochondria-nuclear crosstalk is activated under mitochondrial stress. The signalling pathways activated during mammalian retrograde responses and mitochondrial unfolded protein response (UPR^mt) have not yet been clarified, yet the activation of certain signalling and transcription factors has been observed. The UPR^mt is activated by accumulation of unfolded, misfolded or aggregated proteins in the mitochondrial matrix. This is a two-step process that usually involves activation of transcription factors including CCAAT-enhancer-binding protein homologous protein (CHOP). CHOP dimerises with CCAAT-enhancer-binding protein β (C/EBPβ) and binds to and promotes transcription of UPR^mt responsive genes containing a CHOP-C/EBPβ element. This leads to transcription of mitochondrial quality control genes including Hsp60/10. Reterograde signalling is activated by mitochondrial dysfunction including mtDNA/OXPHOS defects and oxidative stress. This triggers activation of cytosolic signalling pathways which lead to activation of transcription factors including RXRA, JNK2, CHOP, NKκB, Akt, mTOR and c-Myc and transcription of nuclear genes that produce adaptive changes in mitochondrial protein levels.

Fig. 3

The autophagic pathway. The isolation membrane is formed in the cytosol and expanded by the conjugation of the Atg family of proteins (Atg proteins 12,7,10 and conjugated Atg 5/12/16). LC3 exists as both LC3-I and LC3-II. (Damaged organelles and proteins with a long half-life are engulfed by the newly formed autophagosome. The double membrane structure is marked by LC3-II (conjugated to phosphatidylethanolamine) on the surface. The autophagosome fuses with the lysosome under low pH conditions to form the lytic vesicle the autolysosome. Within this compartment organelles and proteins are degraded by lysosomal hydrolyses. Schematic not drawn to scale.

Fig. 4

The mitophagy pathway. Under normal cell homeostasis PINK1 is imported in a membrane potential dependent manner. It localises to the IMM where it is cleaved by PARL. Loss of membrane potential (dashed red line) ensures PINK1 cannot be imported and is trapped at the TOM complex. This recruits the E3 ubiquitin ligase Parkin which ubiquitinates proteins on the cytoplasmic surface of the mitochondria. Ubiquitination of VDAC 1 recruits the adaptor protein p62/SQSTM1 which further binds LC3 and mediates recruitment of the phagophore. This mitochondrion is subsequently degraded by the autophagic pathway.