Division versus Fusion: Dnm1p and Fzo1p Antagonistically Regulate Mitochondrial Shape

Abstract

In yeast, mitochondrial division and fusion are highly regulated during growth, mating and sporulation, yet the mechanisms controlling these activities are unknown. Using a novel screen, we isolated mutants in which mitochondria lose their normal structure, and instead form a large network of interconnected tubules. These mutants, which appear defective in mitochondrial division, all carried mutations in DNM1, a dynamin-related protein that localizes to mitochondria. We also isolated mutants containing numerous mitochondrial fragments. These mutants were defective in FZO1, a gene previously shown to be required for mitochondrial fusion. Surprisingly, we found that in dnm1 fzo1 double mutants, normal mitochondrial shape is restored. Induction of Dnm1p expression in dnm1 fzo1 cells caused rapid fragmentation of mitochondria. We propose that dnm1 mutants are defective in the mitochondrial division, an activity antagonistic to fusion. Our results thus suggest that mitochondrial shape is normally controlled by a balance between division and fusion which requires Dnm1p and Fzo1p, respectively.

Could the low level of expression of the gene encoding skeletal muscle mitofusin-2 account for the metabolic inflexibility of obesity?

“…In yeast, selective inhibition of either processes significantly modifies mitochondrial size and interconnectivity [23,24]. Among the best-known proteins involved in mitochondrial dynamics are Fzo/mitofusin, a transmembrane GTPase involved in fusion [25], and Dnm1p/dynamin-related protein 1, a dynamin-related protein involved in fission [26].…”

Mitochondrial dynamics and division in budding yeast

“…Subsequent studies (described above) suggested that loss of Dnm1p function blocked mitochondrial fission but allowed the fusion of mitochondrial tips to continue, resulting in the formation of elaborate net-like structures [9,10]. Most importantly, the mitochondrial fragmentation induced by a fzo1 mutation no longer occurred in cells containing a dnm1 mutation [9,10].…”

“…The fission and fusion of the inner and outer mitochondrial membranes occur in tandem, although the mechanisms by which this coordination is accomplished are not understood. Fission can occur within a tubule or at a branchpoint in the reticulum and is regulated by a GTPase called Dnm1p [8][9][10]. Fusion always occurs between two mitochondrial tips or between the tip and the side of a tubule, and is regulated by the transmembrane GTPase Fzo1p [11,12].…”

“…In dnm1 mutant cells, mitochondrial fission is abolished but fusion of mitochondrial tips continues, resulting in the formation of elaborate 'net-like' structures ( Fig. 3, left) [9,10]. By contrast, mitochondrial networks rapidly fragment in fzo1 mutant cells because mitochondrial fusion is blocked but fission continues unopposed (Fig.…”

Mitochondrial factors with dual roles in death and survival

“…In addition to Drp1/Dnm1, a dynamin-like GTPase, three other proteins were identified in yeast that are required for normal mitochondrial fission, Fis1, Mdv1/ Net2 and Caf4 (Bleazard et al, 1999;Sesaki and Jensen, 1999;Jensen et al, 2000;Shaw and Nunnari, 2002;Griffin et al, 2005). A critical role for each of these factors in yeast mitochondrial fission is evident from the fact that deletion of any one of them results in fusion of normally tubular mitochondria into continuous nets.…”