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The BBSome regulates mitochondria dynamics and function
Deng-Fu Guo1, Ronald A Merrill2, Lan Qian3
1Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA, USA; Veterans Affairs Health Care System, Iowa City, IA, USA.
Molecular Metabolism
|December 13, 2022
Summary
The Bardet-Biedl syndrome (BBS) complex regulates mitochondria function and dynamics. Loss of BBSome causes mitochondrial defects, leading to BBS symptoms, which can be improved by modulating DRP1 activity.
Area of Science:
- Mitochondrial biology
- Cellular and molecular biology
- Genetics and disease mechanisms
Background:
- Mitochondria are crucial for cellular metabolism and physiological functions.
- The Bardet-Biedl syndrome (BBS) complex, comprising eight BBS proteins, is implicated in various cellular processes.
- Understanding BBSome's role in mitochondrial regulation is essential for BBS pathophysiology.
Purpose of the Study:
- To investigate the role of the BBSome in controlling mitochondrial dynamics and function.
- To elucidate the mechanisms by which BBSome influences mitochondrial health.
- To explore therapeutic targets for BBS-related mitochondrial dysfunction.
Main Methods:
- Generated a Bbs1 gene knockout hypothalamic N39 neuronal cell line using CRISPR/Cas9.
- Analyzed BBSome-deficient mice, with and without AKAP1 gene deletion.
- Utilized a multidisciplinary approach including cell lines, patient-derived fibroblasts, and mouse models.
Main Results:
- BBSome disruption leads to mitochondrial hyperfusion and functional abnormalities, including reduced oxygen consumption and altered calcium handling.
- BBSome regulates dynamin-like protein 1 (DRP1) activity by controlling its phosphorylation and mitochondrial translocation.
- Deletion of AKAP1 normalized mitochondrial defects and improved BBS-related phenotypes like neuroanatomical abnormalities, metabolic alterations, and obesity.
Conclusions:
- The BBSome plays a critical role in modulating mitochondrial function.
- Mitochondrial dysfunction is a key disease mechanism in Bardet-Biedl syndrome.
- Targeting DRP1 activity offers a potential therapeutic strategy for BBS.
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