Journal article
The BBSome regulates mitochondria dynamics and function
Molecular metabolism (Germany), Vol.67, 101654
01/2023
DOI: 10.1016/j.molmet.2022.101654
PMCID: PMC9792363
PMID: 36513220
Abstract
The essential role of mitochondria in regulation of metabolic function and other physiological processes has garnered enormous interest in understanding the mechanisms controlling the function of this organelle. We assessed the role of the BBSome, a protein complex composed of eight Bardet-Biedl syndrome (BBS) proteins, in the control of mitochondria dynamic and function.
We used a multidisciplinary approach that include CRISPR/Cas9 technology-mediated generation of a stable Bbs1 gene knockout hypothalamic N39 neuronal cell line. We also analyzed the phenotype of BBSome deficient mice in presence or absence of the gene encoding A-kinase anchoring protein 1 (AKAP1).
Our data show that the BBSome play an important role in the regulation of mitochondria dynamics and function. Disruption of the BBSome cause mitochondria hyperfusion in cell lines, fibroblasts derived from patients as well as in hypothalamic neurons and brown adipocytes of mice. The morphological changes in mitochondria translate into functional abnormalities as indicated by the reduced oxygen consumption rate and altered mitochondrial distribution and calcium handling. Mechanistically, we demonstrate that the BBSome modulates the activity of dynamin-like protein 1 (DRP1), a key regulator of mitochondrial fission, by regulating its phosphorylation and translocation to the mitochondria. Notably, rescuing the decrease in DRP1 activity through deletion of one copy of the gene encoding AKAP1 was effective to normalize the defects in mitochondrial morphology and activity induced by BBSome deficiency. Importantly, this was associated with improvement in several of the phenotypes caused by loss of the BBSome such as the neuroanatomical abnormalities, metabolic alterations and obesity highlighting the importance of mitochondria defects in the pathophysiology of BBS.
These findings demonstrate a critical role of the BBSome in the modulation of mitochondria function and point to mitochondrial defects as a key disease mechanism in BBS.
Details
- Title: Subtitle
- The BBSome regulates mitochondria dynamics and function
- Creators
- Deng-Fu GuoRonald A Merrill - University of IowaLan Qian - University of IowaYing Hsu - Veterans Affairs Health Care System, Iowa City, IA, USAQihong Zhang - University of IowaZhihong Lin - University of IowaDaniel R Thedens - University of IowaYuriy M Usachev - University of IowaIsabella GrumbachVal C SheffieldStefan StrackKamal Rahmouni
- Resource Type
- Journal article
- Publication Details
- Molecular metabolism (Germany), Vol.67, 101654
- DOI
- 10.1016/j.molmet.2022.101654
- PMID
- 36513220
- PMCID
- PMC9792363
- NLM abbreviation
- Mol Metab
- ISSN
- 2212-8778
- eISSN
- 2212-8778
- Language
- English
- Electronic publication date
- 12/10/2022
- Date published
- 01/2023
- Academic Unit
- Electrical and Computer Engineering; Pathology; Medical Genetics and Genomics; Anesthesia; Roy J. Carver Department of Biomedical Engineering; Radiology; Molecular Physiology and Biophysics; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine; Ophthalmology and Visual Sciences
- Record Identifier
- 9984333013402771
Metrics
15 Record Views