Fussy mitochondria fuse in response to stress

When cells become committed to apoptosis, they shatter their mitochondrial networks through the actions of the mitochondrial fission protein DRP1. Massive fragmentation of mitochondria facilitates simultaneous release of cytochrome c from all mitochondria within a cell, thus promoting further progression along the apoptotic pathway. In this issue, Tondera et al (2009) describe a new process with the opposite effect. When cells are subjected to modest levels of stress (well below levels needed to induce apoptosis), their mitochondria fuse to each other forming a closed network, similar to networks observed when mitochondrial fission is blocked. Stress-induced mitochondrial hyperfusion (SIMH), as this process was called, might counter stress by optimizing mitochondrial ATP production. Mitochondria of healthy cells continually divide and fuse with each other (Okamoto and Shaw, 2005; Chan, 2006; Hoppins et al, 2007). Mitochondrial fission facilitates the redistribution of mitochondria in response to local changes in the demand for ATP and it allows for disposal of faulty mitochondrial fragments through mitophagy, whereas mitochondrial fusion promotes exchange of mtDNA and other vital components, thus reinvigorating the mitochondrial network. Mitochondrial fission and fusion processes are mediated by a series of dynamin family members. Fission is mediated by the dynamin-related protein DRP1. Mutations in the gene coding for this protein give rise to a highly interconnected network of mitochondria. Fusion is mediated by the dynamin-related proteins MFN1 and MFN2 at the mitochondrial outer membranes and the dynamin-related protein OPA1 at the mitochondrial inner membranes. Mutations in the genes coding for these proteins give rise to fragmented mitochondria, because fission still occurs while fusion is blocked. Mutations in the genes coding for the mitochondrial fusion proteins are also responsible for two human diseases. Patients with a heterozygous mutation in MFN2 develop a peripheral neuropathy called Charcot–Marie–Tooth disease (CMT-2A) and patients with heterozygous mutations in OPA1 develop dominant optic atrophy (DOA) through progressive loss of retinal ganglion cells. The severity of heterozygous mutations in humans and the lethality of homozygous mutations in mice show that mitochondrial fission and fusion processes are crucially important for cell survival (Chan, 2006; Davies et al, 2007). The rates of mitochondrial fission and fusion vary between cell types and different growth conditions, but they are usually balanced within a cell. However, the rate of fission does increase markedly without a compensating increase in the rate of fusion when cells become committed to apoptosis (Suen et al, 2008). Increased fission in apoptotic cells coincides with the release of cytochrome c and mutations in the genes for the fission protein DRP1 can delay the release of cytochrome c, suggesting that apoptotic cytochrome c release is intimately connected with mitochondrial fission. Tondera et al (2009) now add a new twist to this plot with their discovery of a pathway that they call Stress-induced mitochondrial hyperfusion (SIMH) pathway. They show that treatments with low levels of toxic agents such as cycloheximide, UV irradiation or actinomycin D have the opposite effect of fullblown apoptosis-inducing treatments. Instead of inducing mitochondrial fragmentation as observed in apoptotic cells, these treatments cause mitochondria to fuse into a closed network, similar to networks observed in cells with mitochondrial fission defects (Figure 1). This closed network confers some degree of