Mitochondrial dynamics and mitochondrial quality control

Abstract

Mitochondria are cellular energy powerhouses that play important roles in maintaining cell survival, cell death and cellular metabolic homeostasis. Timely removal of damaged mitochondria via autophagy (mitophagy) is thus critical for cellular homeostasis and function. Mitochondria are reticular organelles that have high plasticity for their dynamic structures and constantly undergo fission and fusion as well as movement through the cytoskeleton. In this review, we discuss the most recent progress on the molecular mechanisms and roles of mitochondrial fission/fusion and mitochondrial motility in mitophagy. We also discuss multiple pathways leading to the quality control of mitochondria in addition to the traditional mitophagy pathway under different conditions.

Keywords: Autophagy; Mitochondrial spheroids; Mitophagy; Parkin.

Graphical abstract

Fig. 1

Mitochondrial fusion and fission in mammalian cells. (A) Mitochondrial fusion is mediated by large dynamin-related GTPase proteins Mfn1, Mfn2 and OPA1. Outer mitochondria membrane (OM) fusion is mediated by Mfn1 and Mfn2, whereas inner mitochondria membrane (IM) fusion is mediated by OPA1. (B) Mitochondria fission requires the recruitment of Drp1 from cytosol to mitochondria. Drp1 is also a dynamin-related GTPase protein that binds to four Drp1 receptor proteins Fis1, Mff, MID49 and MID51, which are mitochondria OM proteins.

Fig. 2

Regulation of mitochondrial motility. Mitochondria are transported on cytoskeleton microtubules by molecular motor proteins kinesin and dynein. Milton acts as an adapter molecule to link the motor proteins to the outer mitochondrial membrane protein miro, and kinesin transports mitochondria towards the plus end of microtubules whereas dynein transports mitochondria to the minus end of microtubules. When intracellular calcium levels rise, kinesin is dissociated from the Milton–miro complex and then binds to SNPH. SNPH inhibits the ATPase activity of kinesin to block the movement of mitochondria.

Fig. 3

Molecular events for Parkin-dependent mitophagy. When mitochondria are depolarized in response to various insults, Parkin is translocated to the outer membrane of mitochondria. This process is regulated by PINK1, which is stabilized on depolarized mitochondria due to the inactivation of the mitochondrial protease PARL. Pink1 is also stabilized by the outer mitochondrial membrane protein TOMM7 but de-stabilized by SIAH3, a mitochondrial resident protein. PINK1 either directly phosphorylates Parkin or ubiquitin to promote Parkin translocation or its ligase activity. Cytosolic HSPA1L also promotes, whereas BAG4 inhibits, Parkin mitochondrial translocation. Once Parkin translocates to mitochondria, it promotes selective mitophagy through mitochondrial ubiquitination and recruitment of autophagy receptor proteins such as p62 and optineurin, which further recruit LC3 positive autophagosomes.

Fig. 4

Molecular events for Parkin-independent mitophagy. In the absence of Parkin, BNIP3, NIX, FUNDC1 or cardiolipin directly interact with LC3 and recruit autophagosomes to damaged mitochondria. Moreover, other E3 ubiquitin ligases such as SMURF1 and MUL1 can also promote mitochondrial ubiquitination, p62 mitochondrial targeting and mitophagy.

Fig. 5

Mitochondria derived vesicles and mitochondrial spheroids. Under certain conditions, mitochondria can undergo direct remodeling to form mitochondrial spheroids, which are regulated by Mfn1 and Mfn2. Mitochondrial spheroids then further acquire lysosomal markers, possibly through fusion with lysosomes. Small vesicles that contain a subset group of mitochondrial proteins are generated from damaged mitochondria to form MDVs. The segregation of mitochondria to form MDVs is also regulated by Pink1 and Parkin. MDVs are fused with late endosomes and multivesicular bodies and then delivered to lysosomes where they are eventually degraded. Both the formation of mitochondrial spheroids and MDVs are independent of canonical autophagy machinery.