Proteolytic Processing of OPA1 Links Mitochondrial Dysfunction to Alterations in Mitochondrial Morphology

Abstract

Many muscular and neurological disorders are associated with mitochondrial dysfunction and are often accompanied by changes in mitochondrial morphology. Mutations in the gene encoding OPA1, a protein required for fusion of mitochondria, are associated with hereditary autosomal dominant optic atrophy type I. Here we show that mitochondrial fragmentation correlates with processing of large isoforms of OPA1 in cybrid cells from a patient with myoclonus epilepsy and ragged-red fibers syndrome and in mouse embryonic fibroblasts harboring an error-prone mitochondrial mtDNA polymerase ␥. Furthermore, processed OPA1 was observed in heart tissue derived from heart-specific TFAM knock-out mice suffering from mitochondrial cardiomyopathy and in skeletal muscles from patients suffering from mitochondrial myopathies such as myopathy encephalopathy lactic acidosis and stroke-like episodes. Dissipation of the mitochondrial membrane potential leads to fast induction of proteolytic processing of OPA1 and concomitant fragmentation of mitochondria. Recovery of mitochondrial fusion depended on protein synthesis and was accompanied by resynthesis of large isoforms of OPA1. Fragmentation of mitochondria was prevented by overexpressing OPA1. Taken together, our data indicate that proteolytic processing of OPA1 has a key role in inducing fragmentation of energetically compromised mitochondria. We present the hypothesis that this pathway regulates mitochondrial morphology and serves as an early response to prevent fusion of dysfunctional mitochondria with the functional mitochondrial network.

Loss of HtrA2/Omi activity in non-neuronal tissues of adult mice causes premature aging

“…12 The activity of OPA1 is regulated by proteolytic cleavage. Paraplegin, YME1L and OMA1 proteases have all been shown to cleave OPA1, [13][14][15][16][17] thus implicating them in the regulation of mitophagy. The mitochondrial rhomboid protease presenilin-associated rhomboid-like (PARL) is also implicated in regulating mitophagy by cleaving PINK1, 18,19 a kinase required for mitophagy.…”

A cut short to death: Parl and Opa1 in the regulation of mitochondrial morphology and apoptosis

“…For example, it has been reported that Paraplegin, an IMM mAAA metalloprotease, participates in the cleavage of Opa1 to produce a short isoform that is fusion incompetent. 79,80 It should be noted that Paraplegin faces the matrix and that the mitochondrial processing peptidase already trims most of the matrix residues of Opa1. 81 At this stage a plausible scenario deserving further investigation is that Paraplegin and Parl somehow cooperate in the cleavage of Opa1.…”

Quality control of mitochondria during aging: Is there a good and a bad side of mitochondrial dynamics?

“…Aging hypothesis: Deceleration of fusionfission cycles improves mitochondrial quality control Microscopic investigations revealed that mitochondria are organized within a highly dynamic network that is governed by mitochondria undergoing cycles of fusion and fission that result in the mixing of their molecular content [28][29][30][31][32]. Mitochondrial dynamics and consequently changes in mitochondrial morphology are regulated at multiple levels including limited proteolysis, ubiquitinylation, phosphorylation, sumoylation, and disulfide formation of critical fusion and/or fission factors [20,[33][34][35][36][37][38][39][40][41][42][43][44].…”

“…In this context it is important to note that it was shown in yeast as well as in mammalian cells that the bioenergetic state of mitochondria is linked to the mitochondrial morphology [41,42,45,46]. When mitochondrial function is impaired, the fusion machinery is inactivated, e.g.…”

“…When mitochondrial function is impaired, the fusion machinery is inactivated, e.g. via stress-induced proteolytic processing of the fusion factor OPA1 and/or by ubiquitinylation and proteasome-dependent degradation of Mfn2 in mammals [41][42][43][44]. In this way dysfunctional mitochondria become spatially separated from the intact network and, importantly, distinguishable from intact mitochondria.…”