ER-associated CTRP1 regulates mitochondrial fission via interaction with DRP1

Seong Keun Sonn,Goo Taeg Oh,David C Chan,Kunsoo Rhee,Seungwoon Seo,Kyung S Lee,Hsiuchen Chen,Jaemoon Yang,Young Yang,Ki Sook Oh

doi:10.1038/s12276-021-00701-z

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.

Highlights

C1q/TNF-related protein 1 (CTRP1) belongs to the C1q/TNF family, the members of which have four structurally distinct domains: a signal peptide at the N-terminus, a short variable region, a collagenous domain and aC-terminal globular domain
Further analyses using ectopic expression of GFP-tagged CTRP1 showed that GFP–CTRP1 localized to the endoplasmic reticulum (ER) and to mitochondrial fission sites in living cells (Supplementary Fig. 1f)
We found that the CTRP1 mutants lacking the N-terminal domain localized to the cytosol, whereas those lacking the C-terminal C1q domain localized to the ER (Supplementary Fig. 3b and d)

Summary

Introduction

CTRP1 belongs to the C1q/TNF family, the members of which have four structurally distinct domains: a signal peptide at the N-terminus, a short variable region, a collagenous domain and aC-terminal globular domain. CTRP1 belongs to the C1q/TNF family, the members of which have four structurally distinct domains: a signal peptide at the N-. CTRP1 has been shown to regulate vascular function[10,11,12] and protect against acute ischemic injury in the heart[13]. CTRP1 levels were reportedly increased in the sera of hypertensive patients, and CTRP1 has been shown to stimulate aldosterone production and plays a role in blood pressure homeostasis[14,15]. These findings suggest that the secreted form of CTRP1 plays important roles in regulating metabolic and cardiovascular functions.

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Results

Conclusion