New insights into mitochondrial fusion

Abstract

Fusion controls mitochondrial morphology and is important for normal mitochondrial function, including roles in respiration, development, and apoptosis. Key components of the mitochondrial fusion machinery have been identified, allowing an initial dissection of its molecular mechanism. Outer and inner membrane fusion events are coordinately coupled but are mechanistically distinct. Mitofusins are mitochondrial GTPases that likely mediate outer membrane fusion. The dynamin-related protein OPA1/Mgm1p is required for inner membrane fusion and maintenance of normal cristae structure. We highlight recent findings that have advanced our understanding of the mechanism, function, and regulation of mitochondrial fusion.

Figure 1

Schematic structures of mitochondrial GTPases involved in mitochondrial fusion in mammals and budding yeast. These proteins all contain a GTPase domain and hydrophobic heptad repeat (HR) regions. Mitofusins (Mfn1/Mfn2) and Fzo1p also contain a bipartite transmembrane domain (TM), whereas OPA1/Mgm1p has a mitochondrial targeting sequence (MTS), putative membrane-spanning segments (TM?), and the middle and GED domains typical of dynamin family members.

Figure 2

The core mitochondrial fusion machinery and potential regulators. The HR2 region of Mfn1 forms an anti-parallel coiled coil and tethers the outer membranes of mitochondria together in trans. Later steps in outer membrane fusion require its GTPase activity. MitoPLD might act downstream of the tethering step to bring the membranes closer together. After outer membrane fusion, OPA1 may mediate inner membrane fusion, perhaps by forming oligomers in trans. OPA1 is also important in cristae structure. Bax and Bak might regulate the fusion activity of Mfn2. OPA1 activity depends on proteolytic activity; candidate proteases include the m-AAA protease paraplegin and the rhomboid protease PARL.