MCART1 (SLC25A51) deficiency exacerbates mitochondrial dysfunction during MPP+-induced complex I stress.
TL;DR
It is shown that loss of MCART1 exacerbates mitochondrial dysfunction under physiological conditions, and that MCART1 contributes to maintaining membrane potential, preventing ATP depletion, and suppressing ROS accumulation in MPP+-treated neuronal cells.
Abstract
Mitochondrial NAD+ homeostasis, sustained by the inner membrane transporter MCART1, is critical for oxidative metabolism and stress resilience. Inhibition of complex I by 1-methyl-4-phenylpyridinium (MPP+) triggers metabolic collapse and mitochondrial dysfunction, yet whether MCART1 provides a protective gatekeeping function against the MPP+ toxin remains unclear. Here, we show that loss of MCART1 exacerbates mitochondrial dysfunction under physiological conditions, and that MCART1 contributes to maintaining membrane potential, preventing ATP depletion, and suppressing ROS accumulation in MPP+-treated neuronal cells. We identify key NAD+-binding residues within the predicted substrate-binding pocket. Mutation of these residues uncouples MPP+ resistance from constitutive NAD+ transport, defining a structural determinant required for the stress-responsive gatekeeping function of MCART1. These findings establish that MCART1 acts as a conditionally indispensable protector of mitochondrial integrity during complex I poisoning, and reveal that failure of this NAD+ influx pathway drives metabolic collapse in the MPP+ toxin model relevant to Parkinson's disease.