CMT 2A: Mitochondrial Fragmentation Leads to Intracellular Acidification in Caen

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Mol Biol Cell. 2010 May 5

Mitochondrial Fragmentation Leads to Intracellular Acidification in

Caenorhabditis elegans and Mammalian Cellsdrial .

D, Nehrke K.

Departments of Biochemistry, Medicine, and Pharmacology and Physiology,

University of Rochester Medical Center, Rochester, NY 14642.

Abstract

Monitoring Editor: M. Bishr y Mitochondrial structural dynamics are

regulated through the opposing processes of membrane fission and fusion, which

are conserved from yeast to man. The chronic inhibition of mitochondrial fusion

as a result of genetic mutation is the cause of human autosomal dominant optic

atrophy (ADOA) and Charcot-Marie-Tooth syndrome type 2A (CMT-2A).

Here, we demonstrate that genetic fragmentation of the mitochondrial network in

Caenorhabditis elegans induces cellular acidification in a broad range of

tissues from the intestine, to body wall muscles, and neurons. Genetic epistasis

analyses demonstrate that fragmentation itself, and not the loss of a particular

protein, leads to acidosis, and the worm's fitness matches the extent of

acidification.

We suggest that fragmentation may cause acidification through two distinct

processes: oxidative signaling following the loss of the ability of the

mitochondrial inner membrane to undergo fusion, and lactic acidosis following

the loss of outer membrane fusion.

Finally, experiments in cultured mammalian cells demonstrate a conserved link

between mitochondrial morphology and cell pH homeostasis. Taken together these

data reveal a potential role for acidosis in the differing etiology of diseases

associated with mitochondrial morphology defects such as ADOA and CMT-2A.