Novel components of an active mitochondrial K(+)/H(+) exchange.

[wolf-hirschhorn syndrome]

Defects of the mitochondrial K (+)/H (+) exchanger (KHE ) result in increased matrix K (+) content , swelling , and autophagic decay of the organelle . We have previously identified the yeast Mdm 38 and its human homologue LETM 1 , the candidate gene for seizures in Wolf-Hirschhorn syndrome , as essential components of the KHE . In a genome-wide screen for multicopy suppressors of the pet (-) (reduced growth on nonfermentable substrate ) phenotype of mdm 38 Delta mutants , we now characterized the mitochondrial carriers PIC 2 and MRS 3 as moderate suppressors and MRS 7 and YDL 183 c as strong suppressors . Like Mdm 38 p , Mrs 7 p and Ydl 183 cp are mitochondrial inner membrane proteins and constituents of approximately 500 -kDa protein complexes . Triple mutant strains (mdm 38 Delta mrs 7 Delta ydl 183 cDelta ) exhibit a remarkably stronger pet (-) phenotype than mdm 38 Delta and a general growth reduction . They totally lack KHE activity , show a dramatic drop of mitochondrial membrane potential , and heavy fragmentation of mitochondria and vacuoles . Nigericin , an ionophore with KHE activity , fully restores growth of the triple mutant , indicating that loss of KHE activity is the underlying cause of its phenotype . Mdm 38 p or overexpression of Mrs 7 p , Ydl 183 cp , or LETM 1 in the triple mutant rescues growth and KHE activity . A LETM 1 human homologue , HCCR-1 /LETMD 1 , described as an oncogene , partially suppresses the yeast triple mutant phenotype . Based on these results , we propose that Ydl 183 p and the Mdm 38 p homologues Mrs 7 p , LETM 1 , and HCCR-1 are involved in the formation of an active KHE system .

Diseases
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Diseases presenting "growth on nonfermentable substrate" symptom

wolf-hirschhorn syndrome

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