The interplay between mitochondrial dynamics and mitophagy

Abstract

Mitochondrial dynamics and mitophagy are recognized as two critical processes underlying mitochondrial homeostasis. Morphological and bioenergetic characterization of the life cycle of an individual mitochondrion reveals several points where fusion, fission, and mitophagy interact. Mitochondrial fission can produce an impaired daughter unit that will be targeted by the autophagic machinery. Mitochondrial fusion, on the other hand, may serve to dilute impaired respiratory components and thereby prevent their removal. The inverse dependency of fusion and mitophagy on membrane potential allows them to act as complementary rather than competitive fates of the daughter mitochondrion after a fission event. We discuss the interplay between mitochondrial dynamics and mitophagy in different tissues and in different disease models under both stress-induced and steady-state conditions.

FIG. 1.

An example of a fission event that yields an ∼9 mV difference between the two daughter mitochondria. The pseudocolor represents the membrane potential and is derived from a ratio image of TMRE and matrix-targeted photoactivatable (mtPA) GFP. The pseudocolored image depicts two time spots, 60 s before fission and 160 s after fission. Scale bar: 2 μm. Charts of mitochondrial membrane potential (Δψ_m) over time under control conditions are shown to the right. Numbers (i)–(iii) depict the three most common changes to membrane during a fission events as observed in INS1 cells. (see text for further details). Data are modified from Twig et al. (110). (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 2.

The in-silico model simulated a population of mitochondria, each containing 10 copies of mitochondrial functional components (representing the mitochondrial DNA, protein, and lipids required to maintain mitochondrial respiratory function). Each copy was classified as either ‘‘intact’’ or ‘‘damaged’’ (nonfunctional). Mitochondria were subjected to a steady rate of random damage that irreversibly converted random copies from intact to damaged. Accordingly, the number of nondamaged copies was used to deduct the level of mitochondrial activity (Δψ_m equivalent) on a 0–1 scale for each mitochondrion in the cell. The plotted cellular mitochondrial activity is generated by summing the activity of 300 mitochondria in each individual cell and then averaging the 100 different cells that are simulated in parallel. Autophagy targets mitochondria with activity level below 0.3, which was found in the solitary phase, as giant mitochondria fail to fuse (14, 77). Selective (a) and nonselective (b) fusion are compared under low and high (fourfold higher) damage rates. Note that, under increased rates of damage, mitochondrial activity is severely reduced if fusion is nonselective. Dotted line in (b) indicates the “selective” case of fusion under low-damage rate shown in (a). Gray bars indicate the physiological range of mitochondrial fusion in INS1 mitochondria under normal conditions. Data are modified from Mouli et al. (72).

FIG. 3.

A schematic illustration of the mitochondrion's life cycle and the roles of mitochondrial dynamics and autophagy in the segregation of dysfunctional mitochondria. The mitochondrion cyclically shifts between a postfusion state (networked) that lasts tens of seconds and a postfission state (solitary) that can last tens of minutes. Following a fission event, the mitochondrion can depolarize and restore an intact potential (thick arrow) or remain in a depolarized level. Sustained Δψ_m depolarization triggers cleavage of Opa1, accumulation of PINK1/Parkin, and reduction in mitofusin capacity. The mitochondrion may spend several hours in this preautophagic state before targeted by the autophagic machinery. Protein compositions during various steps along these pathways are indicated by a relevant close-up, which are also labeled with numbers, corresponding to their location in the scheme. (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).

FIG. 4.

Potential consequences of reduction in the content of PINK1/Parkin accumulation. Reduction in PINK1/Parkin results in decreased product for mitophagy (dashed arrow) and accumulation of mitofusin on damaged mitochondria. The accumulation of mitofusin on damaged mitochondria allows them to reengage in fusion events despite their deprived energetic state, leading to incorporation of potentially toxic material into the mitochondrial pool. Protein composition at selected steps along the path is illustrated beneath in corresponding numbers 1–4. (To see this illustration in color the reader is referred to the web version of this article at www.liebertonline.com/ars).