The mitochondrial intermembrane space protein mitofissin drives mitochondrial fission required for mitophagy

• DOI: 10.1016/j.molcel.2023.04.022
• Publication Date: 2023-05-15T20:11:51Z
• Authors: Tomoyuki Fukuda; Kentaro Furukawa; Tatsuro Maruyama; Shun-ichi Yamashita; Daisuke Noshiro; Chihong Song; Yuta Ogasawara; Kentaro Okuyama; Jahangir Md Alam; Manabu Hayatsu; Tetsu Saigusa; Keiichi Inoue; Kazuho Ikeda; Akira Takai; Lin Chen; Vikramjit Lahiri; Yasushi Okada; Shinsuke Shibata; Kazuyoshi Murata; Daniel J. Klionsky; Nobuo N. Noda; Tomotake Kanki
• Keywords: Mitochondrial intermembrane space; Intermembrane space; Mitochondrial carrier

Mitophagy plays an important role in mitochondrial homeostasis by selective degradation of mitochondria. During mitophagy, mitochondria should be fragmented to allow engulfment within autophagosomes, whose capacity is exceeded by the typical mitochondria mass. However, the known mitochondrial fission factors, dynamin-related proteins Dnm1 in yeasts and DNM1L/Drp1 in mammals, are dispensable for mitophagy. Here, we identify Atg44 as a mitochondrial fission factor that is essential for mitophagy in yeasts, and we therefore term Atg44 and its orthologous proteins mitofissin. In mitofissin-deficient cells, a part of the mitochondria is recognized by the mitophagy machinery as cargo but cannot be enwrapped by the autophagosome precursor, the phagophore, due to a lack of mitochondrial fission. Furthermore, we show that mitofissin directly binds to lipid membranes and brings about lipid membrane fragility to facilitate membrane fission. Taken together, we propose that mitofissin acts directly on lipid membranes to drive mitochondrial fission required for mitophagy.