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Loss of mpv17 affected early embryonic development via mitochondria dysfunction in zebrafish
Wan-Ping Bian1, Shi-Ya Pu1,2, Shao-Lin Xie1
1Chongqing Institute of Green and Intelligent Technology, Chinese Academy of Sciences, 400714, Chongqing, China.
Abstract:
MVP17 encodes a mitochondrial inner-membrane protein, and mutation of human MVP17 can cause mitochondria DNA depletion syndrome (MDDS). However, the underlying function of mpv17 is still elusive. Here, we developed a new mutant with mpv17 knockout by using the CRISPR/Cas9 system. The mpv17-/- zebrafish showed developmental defects in muscles, liver, and energy supply. The mpv17-/- larvae hardly survived beyond a month, and they showed abnormal growth during the development stage. Abnormal swimming ability was also found in the mpv17-/- zebrafish. The transmission electron microscope (TEM) observation indicated that the mpv17-/- zebrafish underwent severe mitochondria dysfunction and the disorder of mitochondrial cristae. As an energy producer, the defects of mitochondria significantly reduced ATP content in mpv17-/- zebrafish, compared to wild-type zebrafish. We hypothesized that the disorder of mitochondria cristae was contributed to the dysfunction of muscle and liver in the mpv17-/- zebrafish. Moreover, the content of major energy depot triglycerides (TAG) was decreased dramatically. Interestingly, after rescued with normal exogenous mitochondria by microinjection, the genes involved in the TAG metabolism pathway were recovered to a normal level. Taken together, this is the first report of developmental defects in muscles, liver, and energy supply via mitochondria dysfunction, and reveals the functional mechanism of mpv17 in zebrafish.
Insights
Mitochondrial protein MVP17 is essential for zebrafish development. Its absence causes severe mitochondrial dysfunction, leading to muscle and liver defects, impaired energy supply, and reduced survival.
Area of Science:
- Mitochondrial Biology
- Zebrafish Models
- Genetic Disease Research
Background:
- MVP17 is a mitochondrial inner-membrane protein.
- Mutations in human MVP17 are linked to mitochondrial DNA depletion syndrome (MDDS).
- The precise function of MVP17 remains largely unknown.
Purpose of the Study:
- To investigate the function of MVP17 using a zebrafish knockout model.
- To elucidate the role of MVP17 in mitochondrial function and organismal development.
- To understand the mechanism underlying MVP17-related mitochondrial dysfunction.
Main Methods:
- Generated an MVP17 knockout zebrafish model using CRISPR/Cas9.
- Phenotypic analysis of mpv17-/- zebrafish, including developmental, growth, and swimming assessments.
- Transmission electron microscopy (TEM) to examine mitochondrial structure.
- Biochemical assays to measure ATP and triglyceride (TAG) content.
- Mitochondrial rescue experiments via microinjection.
Main Results:
- mpv17-/- zebrafish exhibited significant developmental defects in muscles, liver, and energy supply.
- Larvae showed reduced survival rates (<1 month), abnormal growth, and impaired swimming.
- TEM revealed severe mitochondrial dysfunction and disordered mitochondrial cristae.
- ATP and TAG levels were significantly decreased in mpv17-/- zebrafish.
- Microinjection of exogenous mitochondria partially rescued TAG metabolism pathways.
Conclusions:
- MVP17 is crucial for normal mitochondrial function and overall development in zebrafish.
- Disruption of MVP17 leads to mitochondrial dysfunction, impacting energy homeostasis and organ development.
- This study provides the first report of MVP17's functional mechanism in a whole organism model, highlighting its role in muscle, liver, and energy supply.
