Bax/Bak-Dependent Release of DDP/TIMM8a Promotes Drp1-Mediated Mitochondrial Fission and Mitoptosis during Programmed Cell Death

SummaryMitochondrial morphology within cells is controlled by precisely regulated rates of fusion and fission [1–4]. During programmed cell death (PCD), mitochondria undergo extensive fragmentation [5–7] and ultimately caspase-independent elimination through a process known as mitoptosis [8]. Though this increased fragmentation is due to increased fission through the recruitment of the dynamin-like GTPase Drp1 to mitochondria [9, 10], as well as to a block in mitochondrial fusion [11, 12], cellular mechanisms underlying these processes remain unclear. Here, we describe a mechanism for the increased mitochondrial Drp1 levels and subsequent stimulation of mitochondrial fission seen during PCD. We observed Bax/Bak-mediated release of DDP/TIMM8a, a mitochondrial intermembrane space (IMS) protein [13, 14], into the cytoplasm, where it binds to and promotes the mitochondrial redistribution of Drp1, a mediator of mitochondrial fission. Using both loss- and gain-of-function assays, we also demonstrate that the Drp1- and DDP/TIMM8a-dependent mitochondrial fragmentation observed during PCD is an important step in mitoptosis, which in turn is involved in caspase-independent cell death. Thus, following Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP), IMS proteins released comprise not only apoptogenic factors such as cytochrome c involved in caspase activation [15, 16] but also DDP/TIMM8a, which activates Drp1-mediated fission to promote mitochondrial fragmentation and subsequently elimination during PCD