Mitochondrial membrane potential

Morse and colleagues describe the electron transport chain as four complexes and two electron carriers. Complexes I, III and IV pump protons from the matrix into the intermembrane space. This generates the proton-motive force, which has a pH gradient part and a membrane potential part.⁹ Brzezinski, Moe and Ädelroth note that the inner mitochondrial membrane is about two thirds protein. They discuss Blaza and colleagues, who proposed that this density explains why respiratory supercomplexes form.⁴ Brzezinski and colleagues find that role less likely, because only 15 to 30 percent of cytochrome c oxidase is in supercomplexes in mammalian mitochondria.⁴

Protasoni and Zeviani report that import of inner-membrane proteins through TIM22 needs the membrane potential. It acts electrophoretically on the positively charged targeting sequences of these proteins, and ATP does not drive it.³ Wallace (2013) tied the potential to human population history. He reports that the founding mtDNA of macrohaplogroup N carried two polypeptide variants that changed the mitochondrial membrane potential and Ca2+ metabolism.¹ Macrohaplogroup M, which stayed in semi-tropical Southeast Asia, was not founded by distinctive polypeptide variants.¹

Pai and colleagues (2016) analysed transcriptional responses to changes in cell membrane voltage, Vmem. They name mitochondrial membrane potential and the gene bax as targets of Vmem signals in cell death regulation.² They add that how Vmem regulates apoptosis is not well understood.² George and Bates (2022) describe a route through calcium. Sharp rises in cytoplasmic calcium can overload mitochondria and open the permeability transition pore in the inner membrane.⁵ Extreme opening causes swelling, rupture and necrosis. Milder opening can leak cytochrome C and induce apoptosis.⁵

Rottenberg (2023) reviewed reports that the potential falls in aging animals. He notes a recent suggestion that the lower potential is a major cause of aging, because artificially raising it in C. elegans increased lifespan.⁶ He disputes this reading. In his view many observations show a larger fraction of depolarized mitochondria, caused by more activation of the voltage-gated mPTP.⁷ He concludes that the lifespan result is best explained by inhibition of that pore.⁷ Iorio and colleagues (2024) report that transfer of healthy mitochondria into stressed or injured cells helps restore ATP and mitochondrial membrane potential.⁸