Endoplasmic reticulum-associated degradation regulates mitochondrial dynamics in brown adipocytes
Zhangsen Zhou1, Mauricio Torres1, Haibo Sha2
1Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48105, USA.
Science (New York, N.Y.)
|March 21, 2020
Summary
Mitochondria-associated membranes (MAMs) are crucial for ER-mitochondria communication. Loss of the Sel1L-Hrd1 ER-associated degradation (ERAD) complex in brown adipocytes causes mitochondrial dysfunction and cold sensitivity.
Area of Science:
- Cell Biology
- Mitochondrial Biology
- Endoplasmic Reticulum Biology
Background:
- Specialized endoplasmic reticulum (ER) domains, known as mitochondria-associated membranes (MAMs), mediate crucial crosstalk between the ER and mitochondria.
- The Sel1L-Hrd1 protein complex is a key component of ER-associated protein degradation (ERAD), a cellular process for clearing misfolded proteins.
Purpose of the Study:
- To investigate the role of the Sel1L-Hrd1 ERAD complex in the formation of megamitochondria and the structure of MAMs in brown adipocytes.
- To elucidate the impact of ERAD deficiency on mitochondrial dynamics and ER-mitochondria contacts.
Main Methods:
- Utilized three-dimensional high-resolution imaging to analyze mitochondrial morphology and MAMs.
- Investigated the physiological consequences of ERAD deficiency in brown adipocytes using mouse models.
Main Results:
- ERAD deficiency in brown adipocytes led to the formation of pleomorphic megamitochondria with altered MAMs.
- Mice with ERAD-deficient brown adipocytes displayed cold sensitivity and mitochondrial dysfunction.
- ERAD deficiency disrupted ER-mitochondria contacts and mitochondrial dynamics, partly by regulating sigma receptor 1 (SigmaR1) turnover at MAMs.
Conclusions:
- The Sel1L-Hrd1 ERAD complex is essential for maintaining normal ER-mitochondria crosstalk and mitochondrial function in brown adipocytes.
- Dysregulation of ERAD impacts mitochondrial dynamics and cellular adaptation to cold stress.
- This study provides novel molecular insights into the physiological significance of ER-mitochondrial interactions regulated by ERAD.
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