Mitochondrial dynamics and division in budding yeast

Abstract

Mitochondria adopt a variety of different shapes in eukaryotic cells, ranging from multiple, small compartments to elaborate tubular networks. The establishment and maintenance of different mitochondrial morphologies depends, in part, on the equilibrium between opposing fission and fusion events. Recent studies in yeast, flies, worms and mammalian cells indicate that three highmolecular-weight GTPases control mitochondrial membrane dynamics. One of these is a dynamin-related GTPase that acts on the outer mitochondrial membrane to regulate fission. Recently, genetic approaches in budding yeast have identified additional components of the fission machinery. These and other new findings suggest a common mechanism for membrane fission events that has been conserved and adapted during eukaryotic evolution.Although it is generally accepted that mitochondria play key roles in apoptosis, the cell stress response, aging and various genetically inherited diseases, it is only recently that the regulation of mitochondrial morphology has been recognized as an important factor controlling cell function. It is now known that three conserved GTPases, called Dnm1/Drp1/ Dlp1, Fzo/mitofusin and Mgm1/Opa1/Msp1, regulate mitochondrial fission, fusion and membrane structure in many organisms. Moreover, a recent study demonstrated that inhibition of mammalian Drp1 function blocks cell death, suggesting that mitochondrial fission plays an essential role in apoptosis [1]. This finding raises the possibility that Drp1 (and perhaps Fzo-and Mgm1-type) GTPases are targets of signals that determine how mitochondrial membrane morphology changes in response to intracellular and extracellular cues.A comprehensive list of the genes and proteins implicated in mitochondrial membrane dynamics can be found in several excellent reviews [2][3][4]. Here, we describe what is known about the three GTPases that regulate mitochondrial membrane dynamics and highlight new studies in budding yeast that provide insight into the mechanism of mitochondrial fission. Mitochondrial morphology and membrane dynamicsAlthough the mitochondrion is always surrounded by a double membrane, contains a DNA genome and specializes in the synthesis of ATP, studies using vital dyes and the green fluorescent protein indicate that the morphology of this organelle is different in different cell types and organisms [5][6][7]. In some cells, mitochondria appear as small, bean-shaped compartments dispersed throughout the cytoplasm. In others, the organelles form elongated tubules or a single, highly branched reticulum. Mitochondria continuously grow, divide and fuse throughout the life of a cell and it is the frequency of fission events relative to fusion events that largely determines steady-state organelle morphology. NIH Public Access

Mitochondrial factors with dual roles in death and survival

“…Organelle fission may be required to send mitochondria to distant sites where ATP is required, whereas fusion appears to be required for genetic complementation and maintenance of healthy mitochondria. Elegant yeast genetic studies identified two sets of genes, one that facilitates fusion whereas the other facilitates fission (Shaw and Nunnari, 2002). Balanced fusion and fission of mitochondria results in tubular mitochondrial morphology.…”

“…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.…”

“…Yeast Fis1 (18 kDa) is slightly smaller than Bcl-2 family proteins (about the size of viral Bcl-2 proteins). It localizes to the outer mitochondrial membrane via its C-terminal hydrophobic-basic domain with its Nterminus in the cytosol, similar to Bcl-2 (Shaw and Nunnari, 2002;Tieu et al, 2002). Unlike Bcl-2, the three-dimensional structures of yeast, human and mouse Fis1, solved by three different groups, revealed that Fis1 is a tetratricho-peptide repeat (TPR) protein that is most superimposable with one of the TPR motifs in the peroxisomal protein Pex5, but is perhaps the most similar in overall structure and size to the mitochondrial import protein Tom20 (Abe et al, 2000;Suzuki et al, 2003;Dohm et al, 2004).…”

Alternate functions of viral regulators of cell death

“…73 Genetic studies in C. elegans demonstrated that worm Bcl-2, normally an antideath factor, can promote cell death by activating Drp1, a dynamin-like GTPase that was first identified in yeast as a factor that is required for mitochondrial fission. 74,75 The human and yeast homologs of Drp1/Dnm1 also promote programmed cell death in mammalian and yeast cells, respectively. [76][77][78] Like Bax, Drp1 relocalizes to mitochondria during cell death and colocalizes with Bax at mitochondrial constriction sites.…”

Divide et impera: Ca2+ signals, mitochondrial fission and sensitization to apoptosis

“…28,29 The role of dynamins in controlling mitochondrial shape was first identified in yeast, where deletion of specific dynamin genes results in gross alterations of the mitochondrial network and in functional abnormalities including loss of mitochondrial DNA, growth defects and petite strains. 30 In mammalian cells, the cytosolic dynamin-like protein DRP-1 translocates to the mitochondria to promote fission, 31 whereas the mitochondrial integral proteins MFN-1 and -2 and OPA1 regulate fusion. 32,33 Ablation of mfn-1 and -2 in the mouse results in embryonic lethality, 34 loss of function mutations of OPA1 cause dominant optic atrophy Kjer type 1, 35,36 a human disease characterized by loss of retinal ganglionic cells, and knocking down of OPA1 using small RNA interference induces cell death.…”