Author's Personal Copy Review New Insights into the Function and Regulation of Mitochondrial Ssion

In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: a b s t r a c t a r t i c l e i n f o Keywords: Mitochondrial ssion Drp1 Apoptosis Mitophagy Post-translational modi cation Neurodegenerative disease Mitochondrial morphology changes dynamically by coordinated fusion and ssion and cytoskeleton-based transport. Cycles of outer and inner membrane fusion and ssion are required for the exchange of damaged mitochondrial genome DNA, proteins, and lipids with those of healthy mitochondria to maintain robust mi-tochondrial structure and function. These dynamics are crucial for cellular life and death, because they are essential for cellular development and homeostasis, as well as apoptosis. Disruption of these functions leads to cellular dysfunction, resulting in neurologic disorders and metabolic diseases. The cytoplasmic dynamin-related GTPase Drp1 plays a key role in mitochondrial ssion, while Mfn1, Mfn2 and Opa1 are involved in fusion reaction. Here, we review current knowledge regarding the regulation and physiologic relevance of Drp1-dependent mitochondrial ssion: the initial recruitment and assembly of Drp1 on the mitochondrial ssion foci, regulation of Drp1 activity by post-translational modi cations, and the role of mi-tochondrial ssion in cell pathophysiology. Mitochondria are essential organelles for the life and death of eukaryotic cells and participate in oxidative phosphorylation; biogen-esis of iron-sulfur clusters, heme, certain lipids, and amino acids; calcium signaling; and regulation of apoptosis [1 9]. Mitochondria move along cytoskeletal tracks to sites of high-energy demand, and change their overall morphology by fusion and ssion in response to the cellular environment and differentiation [10 13]. Mitochondria proliferate by growth and division, thus their fusion and ssion are important for maintaining mitochondrial number and function. High-molecular weight GTPases are key components involved in regulating the mito-chondrial morphologic dynamics [4 8]; in vertebrates, mitofusin proteins (Mfn1 and Mfn2) of the mitochondrial outer membrane (MOM) regulate MOM fusion [14 18] and mitochondrial inner membrane (MIM) protein Opa1 is involved in MIM fusion, probably coupled with MOM fusion and cristae remodeling [19 21], whereas dynamin-related protein Drp1 (or Dlp1) mostly localizes to the cytoplasm and is recruited to mitochondria to regulate mitochondrial ssion [22 25]. The balance of these opposing events is precisely controlled to maintain the overall architecture and metabolic stability of the mitochondria [26]. …