ReviewMitochondrial fusion and division: Regulation and role in cell viability
Section snippets
Introduction: the dynamic complexity of mitochondrial structure
In addition to their canonical role in ATP generation [1], [2], mitochondria house several other metabolic pathways, including β-oxidation of fatty acids, iron–sulfur clusters biogenesis, and oxygen metabolism. Furthermore, mitochondria are vital for a number of regulatory pathways, including stress-induced or developmental cell death [3], [4], [5] and Ca2+ buffering and signaling [1]. This wide-ranging role of mitochondria is facilitated by the highly regulated compartmentalization of these
Regulation of dynamic remodeling of mitochondria
Key proteins required for mitochondrial fusion include: large GTPases, Mfn1 and Mfn2 (homologues of yeast Fzo1p) [12], [13], and OPA1 (Optic Atrophy protein 1, homologue of yeast Mgm1p) [14], [15], [16]. These proteins can physically interact [17] and appear to act in concert in mitochondrial fusion. The OMM-localized Mfn1 and Mfn2 are required for the initial tethering of fusing mitochondria [18], [19]. The second step of mitochondrial fusion likely requires the physical interaction between
The OMM-associated fusion factors
Two mitofusin proteins, Mfn1 and Mfn2, are expressed in mammalian cells. Although, Mfn1 and Mfn2 have a very high degree of sequence similarity [13], both of these proteins are ubiquitously expressed in most tissues examined. Mfn1 and Mfn2 localize to the OMM, with an N-terminal GTPase and C-terminal coiled-coil domains exposed to the cytoplasmic side of the mitochondria, and a short loop exposed to the intermembrane space. Mfn1 and Mfn2 can form homo- or hetero-oligomers [12], [18], [19] that
Fis1 and mitochondrial fission factor (Mff): C-tail anchored proteins with roles in mitochondrial division
Fis1 is an OMM anchored protein, ubiquitously expressed throughout different tissues [50], [51]. In yeast this protein is required for mitochondrial division and serves as mitochondrial receptor for the recruitment of the Dnm1p, the yeast homologue of Drp1. Although the role of Fis1 in division of mammalian mitochondria appears to be conserved [37], [50], [51], [52], the mechanism of Fis1 action is not clear. For example, although Fis1 and Drp1 can be co-immunoprecipitated from crosslinked
Critical role of mitochondrial network equilibrium for cell survival
Aberrations in mitochondrial dynamics appear to be generally associated with various neurodegenerative diseases [67]. Mutations of fusion proteins OPA1 and Mfn2, and likely defective mitochondrial fusion, are associated with two neurodegenerative diseases, autosomal dominant optic atrophy (ADOA) [14], [15], [68], [69], [70], [71], [72] and Charcot–Marie–Tooth peripheral neurodegeneration (CMT) [73], [74], [75], respectively (Table 1). Furthermore, Purkinje cells lacking Mfn2 degenerate in
Concluding remarks
Studies indicating that mitochondrial fusion and division are vital for function and development of the organism emphasize a critical need for further research of these processes. As discussed above, although several key fusion and division factors have been identified, the coordination and regulation of these proteins is only preliminarily characterized. In addition, further characterization of the molecular crosstalk between mitochondrial morphogenesis proteins and proteins vital for other
Acknowledgments
The authors would like to thank Dr. J. Kao and P. Wright for comments on the manuscript. The authors also gratefully acknowledge financial support from National Institute of General Medical Science RO1 GM083131 (M.K).
References (103)
- et al.
Role of mitochondrial remodeling in programmed cell death in Drosophila melanogaster
Dev Cell
(2007) - et al.
Mitochondrial death pathways in yeast and mammalian cells
Biochim Biophys Acta
(2008) - et al.
Mitochondrial dynamics and division in budding yeast
Trends Cell Biol
(2002) - et al.
Mitochondrial dynamics and disease, OPA1
Biochim Biophys Acta
(2006) - et al.
Activated mitofusin 2 signals mitochondrial fusion, interferes with Bax activation, and reduces susceptibility to radical induced depolarization
J Biol Chem
(2005) - et al.
Identification of a novel mitochondrial complex containing mitofusin 2 and stomatin-like protein 2
J Biol Chem
(2007) - et al.
SLP-2 interacts with prohibitins in the mitochondrial inner membrane and contributes to their stability
Biochim Biophys Acta
(2008) - et al.
hFis1, a novel component of the mammalian mitochondrial fission machinery
J Biol Chem
(2003) - et al.
Bax- or Bak-induced mitochondrial fission can be uncoupled from cytochrome C release
Mol Cell
(2008) - et al.
Disruption of the phosphatidylserine decarboxylase gene in mice causes embryonic lethality and mitochondrial defects
J Biol Chem
(2005)