Mitochondrial quality control: from molecule to organelle

Abstract

Mitochondria are organelles central to myriad cellular processes. To maintain mitochondrial health, various processes co-operate at both the molecular and organelle level. At the molecular level, mitochondria can sense imbalances in their homeostasis and adapt to these by signaling to the nucleus. This mito-nuclear communication leads to the expression of nuclear stress response genes. Upon external stimuli, mitochondria can also alter their morphology accordingly, by inducing fission or fusion. In an extreme situation, mitochondria are degraded by mitophagy. Adequate function and regulation of these mitochondrial quality control pathways are crucial for cellular homeostasis. As we discuss, alterations in these processes have been linked to several pathologies including neurodegenerative diseases and cancer.

Keywords: ISR; Mitochondrial diseases; Mitochondrial dysfunction; Mitochondrial fission; Mitochondrial fusion; Mitophagy; PINK1; Parkin; UPRmt.

Fig. 1

Mitochondrial retrograde signaling. The mitochondrial integrated stress response (ISR^mt) is regulated by phosphorylation of the elongation transcription factor eIF2α, which enhances the translation of ATF4. The kinases HRI and GCN2 phosphorylate eIF2α (P-eIF2α) following a mitochondrial stress. In addition, the ISR is also part of the mitochondrial unfolded protein response (UPR^mt), activated by misfolded mitochondrial proteins. Moreover, other mechanisms of mito-nuclear communication (mTORC, SIRT1, GPS2) are activated following changes in mitochondrial ROS, NAD, ATP/ADP ratio, calcium (Ca²⁺) or membrane potential (Δψ). Once the transcription factors ATF4, ATF5, ATF2 and/or GPS2 are in the nucleus, they regulate the expression of nuclear stress-response genes

Fig. 2

Mitochondrial dynamics. Mitochondria are dynamic organelles that adapt their network according to cellular requirements. For instance, a decrease of respiration leads to mitochondrial fission and starvation induces fusion. Both processes are regulated by different proteins; dynamin-related protein 1 (DRP1) is involved in fission, meanwhile Mitofusin 1 and Mitofusin 2 (MFN1/2) and optic atrophy 1 (OPA1) allows fusion. OXPHOS = oxidative phosphorylation

Fig. 3

Mitophagy. Mitophagy allows the removal of damaged mitochondria by the PINK/Parkin pathway. When mitochondria are damaged, PINK1 is accumulated on the outer mitochondrial membrane (OMM) where it gets activated and phosphorylates and therefore activates Ubiquitin (Ub) and Parkin. Parkin ubiquitinates different OMM proteins in a feed-forward mechanism, leading to a general mitochondrial ubiquitination. That ubiquitination recruits autophagy receptor proteins (OPTN, p62), and, in turn, autophagosomes into the mitochondria, leading to the induction of autophagy