Fig. 1.

Maintenance of mitochondrial homeostasis. Mitochondrial number and health are under the control of three pathways: biogenesis, fusion-fission cycles and mitochondrial quality control. In healthy cells, these pathways are well balanced. Mitochondrial biogenesis involves mtDNA replication, while fusion promotes mtDNA mixing. Wild type mtDNA is illustrated in blue or green, while mutated mtDNA is indicated in red. Execution of the fusion process requires merging of the outer and inner mitochondrial membranes via the sequential action of the GTPase proteins, OPA1 (purple circles) and the mitofusins, Mfn1 and Mfn2 (yellow circles). Mitochondrial mass is also influenced by the process of fission, a process during which one mitochondrion gives rise to two healthy mitochondria. Fission is controlled by the dynamin-related protein DRP1 protein (black circles) and its receptors, such as Fis1 protein (pink circles), which together constrict the membranes to cause separation of mitochondria. The mitochondrial quality control prevents accumulation of dysfunctional mitochondria exhibiting mitochondrial membrane depolarization, which are targeted by the autophagic machinery for clearance. Healthy mitochondria are attached to microtubules via the kinesin heavy chain (KHC in blue) and the Miro-Milton adaptor complex illustrated by purple and green symbols, respectively. Following mitochondrial membrane depolarization provoked by various insults or increased mutated mtDNA population, PINK1 (pink symbol) accumulates in the outer mitochondrial membrane to recruit Parkin (grey symbol). Subsequently, Miro is phosphorylated resulting in detachment from Milton and microtubules. Parkin promotes ubiquitination (yellow symbol) of Miro and additional mitochondrial proteins, thereby inducing mitophagy with the assistance of autophagosomes (red symbol).