ER-associated CTRP1 regulates mitochondrial fission via interaction with DRP1

Abstract

C1q/TNF-related protein 1 (CTRP1) is a CTRP family member that has collagenous and globular C1q-like domains. The secreted form of CTRP1 is known to be associated with cardiovascular and metabolic diseases, but its cellular roles have not yet been elucidated. Here, we showed that cytosolic CTRP1 localizes to the endoplasmic reticulum (ER) membrane and that knockout or depletion of CTRP1 leads to mitochondrial fission defects, as demonstrated by mitochondrial elongation. Mitochondrial fission events are known to occur through an interaction between mitochondria and the ER, but we do not know whether the ER and/or its associated proteins participate directly in the entire mitochondrial fission event. Interestingly, we herein showed that ablation of CTRP1 suppresses the recruitment of DRP1 to mitochondria and provided evidence suggesting that the ER-mitochondrion interaction is required for the proper regulation of mitochondrial morphology. We further report that CTRP1 inactivation-induced mitochondrial fission defects induce apoptotic resistance and neuronal degeneration, which are also associated with ablation of DRP1. These results demonstrate for the first time that cytosolic CTRP1 is an ER transmembrane protein that acts as a key regulator of mitochondrial fission, providing new insight into the etiology of metabolic and neurodegenerative disorders. Metabolism: When mitochondria grow too big A protein named CTRP1 helps mitochondria, the powerhouses of cells, to divide after they grow too big, and could provide insight into neurodegenerative disorders such as Alzheimer's disease. CTRP1 is known to be involved in metabolic and cardiovascular diseases. The finding that it is also highly expressed in mitochondria-rich tissues such as heart muscle led Goo Taeg Oh at Ewha Womans University and Young Yang at Sookmyung Women's University, both in South Korea, and coworkers to further investigate its function. They found that CTRP1 is highly expressed in the cell's transport system, where it helps to regulate mitochondrial division. CTRP1 deficiency in mice produced abnormally long mitochondria, causing cells to become resistant to programmed cell death, and leading to degeneration of neurons. These results may increase understanding of diseases related to mitochondrial defects.