MCART1 (SLC25A51) deficiency exacerbates mitochondrial dysfunction during MPP+-induced complex I stress
Shiliang Wang1, Peixin Sun1, Yue Zhang1
1Institute for Translational Brain Research, State Key Laboratory of Brain Function and Disorders and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200032, China.
Free Radical Biology & Medicine
|August 10, 2026
Summary
Mitochondrial NAD+ transporter MCART1 protects neuronal cells from MPP+ toxicity by maintaining energy and reducing oxidative stress. Loss of MCART1 function worsens mitochondrial dysfunction, impacting Parkinson's disease models.
Area of Science:
- Mitochondrial biology
- Neurobiology
- Biochemistry
Background:
- Mitochondrial NAD+ homeostasis is vital for cellular energy production and stress resistance.
- The inner mitochondrial membrane transporter MCART1 is implicated in sustaining NAD+ levels.
- The role of MCART1 in protecting against toxins like MPP+, a model for Parkinson's disease, is not fully understood.
Purpose of the Study:
- To investigate the protective role of MCART1 against MPP+-induced mitochondrial dysfunction.
- To elucidate the mechanism by which MCART1 confers resistance to MPP+.
- To identify structural determinants of MCART1's gatekeeping function.
Main Methods:
- Utilized neuronal cell models treated with MPP+ to assess mitochondrial function.
- Quantified changes in membrane potential, ATP levels, and reactive oxygen species (ROS) production.
- Performed site-directed mutagenesis of predicted NAD+-binding residues in MCART1.
Main Results:
- Loss of MCART1 function exacerbated mitochondrial dysfunction and cellular damage under physiological and MPP+-treated conditions.
- MCART1 was found to maintain membrane potential, prevent ATP depletion, and suppress ROS accumulation in MPP+-treated cells.
- Mutating key NAD+-binding residues in MCART1 uncoupled MPP+ resistance from NAD+ transport, revealing a critical structural element for its protective function.
Conclusions:
- MCART1 acts as a crucial gatekeeper, protecting mitochondrial integrity against complex I poisoning by MPP+.
- Failure of MCART1-mediated NAD+ influx contributes to metabolic collapse in models relevant to Parkinson's disease.
- Specific NAD+-binding residues are essential for MCART1's stress-responsive protective function.
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