Mitochondrial fission, fusion, and stress

Abstract

Mitochondrial fission and fusion play critical roles in maintaining functional mitochondria when cells experience metabolic or environmental stresses. Fusion helps mitigate stress by mixing the contents of partially damaged mitochondria as a form of complementation. Fission is needed to create new mitochondria, but it also contributes to quality control by enabling the removal of damaged mitochondria and can facilitate apoptosis during high levels of cellular stress. Disruptions in these processes affect normal development, and they have been implicated in neurodegenerative diseases, such as Parkinson's.

Fig. 1

Fusion rescues stress by allowing functional mitochondria (green) to complement dysfunctional mitochondria (yellow) by diffusion and sharing of components between organelles. Stress-induced hyperfusion yields maximal potential (light green), whereas under relaxed conditions cells are able to segregate the damaged (yellow) ones.

Fig. 2

Autophagy could purify the cellular pool of mitochondria if debris is aggregated and segregated by fission in a subset of mitochondria. If deleterious components (black fibers) are asymmetrically distributed or aggregated, fission could lead to cleansing of daughter mitochondrion (green) by preventing fusion and inducing mitophagy of the impaired ones (yellow).

Fig. 3

PINK1 is constitutively degraded by the inner mitochondrial membrane protease PARL and maintained at low levels on healthy mitochondria. When a mitochondrion becomes damaged to the point of depolarizing the membrane potential across the inner membrane, PINK1 import to the inner membrane is prevented, thereby sequestering it on the outer mitochondrial membrane and away from PARL. PINK1 accumulates there and recruits the E3 ligase Parkin from the cytosol via PINK1 kinase activity. Parkin conjugates ubiquitin (Ub) to a variety of proteins on the outer mitochondrial membrane and mediates the proteosomal elimination of mitofusins 1 and 2. Lastly, Parkin induces autophagic elimination of the dysfunctional mitochondria. This pathway may constitute a quality-control mechanism to eliminate damaged mitochondria. UPS, ubiquitin proteasome system.