Calcium-mediated constriction of mitochondrial inner compartment for efficient mitochondrial division in neuron

Abstract

Proper regulation of mitochondrial function and distribution is critical for neuronal physiology and pathology. For this process, mitochondria dynamically undergo morphological change by controlled fusion and division. While mitochondrial fusion is completed by sequential fusion of outer- (OMM) and inner-membrane, division is solely executed by cytosolic OMM-constricting machinery including actin filament, Drp1 and Dyn2. Although some intra-mitochondrial events promoting division also has been proposed, the underlying molecular mechanism has not been identified. In this study, we reveal spontaneous, transient and repetitive constriction of mitochondrial inner compartment (CoMIC) in neuronal process, which is spatiotemporally linked with mitochondrial division. However, it appears independently of OMM-constricting machinery unlike mitochondrial division. The CoMIC is initiated and potentiated by mitochondrial Ca2+, which induces two synergistic processes: (1) mitochondrial bulging and depolarization by mitochondrial influx of K+, and (2) transient disorganization of OMM-IMM contact by accumulation of cleaved Opa1. Finally, the mitochondrial Ca2+ indirectly promotes mitochondrial division by triggering the CoMIC. Taken together, we first suggest that the CoMIC is a Ca2+-driven priming event on mitochondrial inner compartment for mitochondrial division.