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Effects of MOTS-c on the mitochondrial function of cells harboring 3243 A to G mutant mitochondrial DNA
Chang Ho Ahn1,2, Eun Hye Choi1,2, Byung Soo Kong1,2
1Department of Internal Medicine, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, Republic of Korea.
Abstract:
Mitochondrial derived peptides (MDPs) are a class of peptide encoded in small open reading frames of mitochondrial DNA (mtDNA). MOTS-c, a recently discovered MDP, participates in retrograde signaling from the mitochondria to the nucleus to control cellular metabolism. Humanin, another MDP, has cytoprotective properties and enhances mitochondrial function. However, it has not yet been tested whether MOTS-c can affect mitochondrial function. We investigated the effect of exogenous and endogenous MOTS-c on mitochondrial function in a cybrid cell harboring 3243 A to G mutant mtDNA, which causes significant mitochondrial dysfunction. To test the effects of endogenous MOTS-c, the cybrid cell was transfected with a MOTS-c EGFP expression vector. Exogenous (synthetic) MOTS-c did not show a significant effect on the ATP content or the mRNA and protein levels of the mitochondrial complex in the mutant cybrid cells. Basal and stimulated mitochondrial respiration were also not affected by exogenous MOTS-c. The mutant cybrid cells transfected with the MOTS-c EGFP expression vector stably expressed MOTS-c, but ATP production and mRNA and protein levels of the mitochondrial complex were not affected. In contrast to other MDPs, MOTS-c does not improve mitochondrial dysfunction in cybrid cells with mutant mtDNA, which suggests the heterogeneous nature of MDPs.
Insights
Mitochondrial derived peptides (MDPs) like MOTS-c do not improve mitochondrial dysfunction in cells with mutant mitochondrial DNA. This suggests that different MDPs have varied effects on cellular health.
Area of Science:
- Mitochondrial biology
- Molecular genetics
- Cellular metabolism
Background:
- Mitochondrial derived peptides (MDPs) are encoded by mitochondrial DNA and play roles in cellular processes.
- MOTS-c and Humanin are examples of MDPs with known functions in metabolism and cytoprotection.
- The effect of MOTS-c on mitochondrial function, particularly in the context of mitochondrial dysfunction, remains largely unexplored.
Purpose of the Study:
- To investigate the impact of both exogenous and endogenous MOTS-c on mitochondrial function.
- To assess MOTS-c's effects in a cybrid cell model harboring the 3243 A to G mutant mitochondrial DNA, a known cause of mitochondrial dysfunction.
- To compare MOTS-c's efficacy with other MDPs in improving mitochondrial health.
Main Methods:
- Utilized a cybrid cell model with 3243 A to G mutant mitochondrial DNA.
- Administered exogenous synthetic MOTS-c to the mutant cybrid cells.
- Transfected mutant cybrid cells with a MOTS-c EGFP expression vector to study endogenous MOTS-c effects.
- Assessed ATP content, mitochondrial complex mRNA and protein levels, and mitochondrial respiration (basal and stimulated).
Main Results:
- Exogenous MOTS-c did not significantly alter ATP levels, mitochondrial complex expression, or mitochondrial respiration in mutant cybrid cells.
- Stable expression of endogenous MOTS-c via transfection also failed to improve ATP production or mitochondrial complex function.
- MOTS-c did not ameliorate the mitochondrial dysfunction observed in the cybrid cells with mutant mitochondrial DNA.
Conclusions:
- MOTS-c does not appear to improve mitochondrial dysfunction in cells with the 3243 A to G mutant mitochondrial DNA.
- Unlike other known MDPs, MOTS-c does not exhibit a beneficial effect on mitochondrial function in this specific cellular model.
- These findings highlight the heterogeneous functional properties among different mitochondrial derived peptides.
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