Mitochondrial dynamics and apoptosis

Abstract

In healthy cells, mitochondria continually divide and fuse to form a dynamic interconnecting network. The molecular machinery that mediates this organelle fission and fusion is necessary to maintain mitochondrial integrity, perhaps by facilitating DNA or protein quality control. This network disintegrates during apoptosis at the time of cytochrome c release and prior to caspase activation, yielding more numerous and smaller mitochondria. Recent work shows that proteins involved in mitochondrial fission and fusion also actively participate in apoptosis induction. This review will cover the recent advances and presents competing models on how the mitochondrial fission and fusion machinery may intersect apoptosis pathways.

Figure 1.

Mitochondrial fission machinery. Schematic of the localization of three proteins (Drp1, Fis1, and MARCH5) involved in mitochondrial fission in mammalian cells.

Figure 2.

Outer mitochondrial morphology effects of Endophilin B1 knockdown. Confocal image of Endophilin B1/Bif1/SH3GLB1 knockdown by RNA interference in HeLa cells shows webs of OMM tubules (green) linking fragmented matrix compartments (red). Immunofluorescence of OMM is in green (α-Tom20) and the mitochondrial matrix is shown in red (α-TRAP1) (image by Chunxin Wang).

Figure 3.

Mitochondrial fusion machinery. Schematic of the submitochondrial localization of mammalian proteins involved in mitochondrial fusion in healthy cells, including the mitofusins, OPA1, mitoPLD, and Bak (see key). Insert shows the localization of proteases proposed to function in OPA1 cleavage. Presenilin-associated rhomboid-like (PARL) is one member of the rhomboid family.

Figure 4.

Cytochrome c release during apoptosis. Confocal image of multiple HeLa cells treated with actinomycin D and z-VAD-FMK (caspase inhibitor). Green represents cytochrome c immunofluorescence. (1) Healthy cells with long mitochondria and cytochrome c present in mitochondria. (2) During early stages of apoptosis, mitochondria fragment while some cytochrome c is retained in mitochondria. (3) Progressively later stages of apoptosis also have fragmented mitochondria, but cytochrome c is beginning to become visible in the cytosol. (4) Following complete release, cytochrome c is no longer within the mitochondria (image by Mariusz Karbowski). The time course for cytochrome c has been shown to be relatively fast and complete, indicating that mitochondrial fragmentation occurs immediately prior to or during the cytochrome c release process.

Figure 5.

Competing models of mitochondrial morphogenesis machinery and apoptosis progression. (A) Mitochondrial foci model. From left to right, Bax (orange) translocates to mitochondria and coalesces into foci with Drp1, mitofusins, and Bak (see key), leading to mitochondrial division and release of cytochrome c (small red circles) from mitochondrial stores. (B) Cristae model of apoptosis. Drp1 (yellow) forms constriction sites on the OMM (left), then small amounts of cytochrome c from the intermembrane space are released through Bax/Bak pores (middle). (Right) Finally, cristae undergo remodeling, opening the junctions to release the larger amount of cytochrome c stored within the matrix.