Identification of Rhit as a novel transcriptional repressor of human Mpv17-like protein with a mitigating effect on mitochondrial dysfunction, and its transcriptional regulation by FOXD3 and GABP.

Mpv17-like protein (M-LP) is a protein that has been suggested to be involved in the metabolism of reactive oxygen species. To elucidate the molecular basis of M-LP expression, we recently searched for regulatory elements of M-LP and identified a novel mouse KRAB-containing protein, Rhit (regulator of heat-induced transcription), as a repressor of the transcriptional regulation of M-LP. In this study, we identified zinc-finger protein 205 as a candidate human Rhit (RhitH) and subsequently confirmed its participation in transcriptional regulation of human M-LP (M-LPH). To clarify the functions of RhitH and M-LPH, we searched for cis-regulatory elements in the promoter region of RhitH and identified two transcription factors: forkhead box D3, as a negative regulatory element, and GA-binding protein, one of the key regulators of the mitochondrial electron transport system, as a positive regulatory element. Additionally, it was demonstrated that knockdown of RhitH or overexpression of M-LPH reduces the generation of intracellular H(2)O(2) and loss of mitochondrial membrane potential caused by an inhibitor of the respiratory chain, antimycin A. These results suggest that M-LPH functions to protect cells from oxidative stress and/or initiation of the mitochondrial apoptotic cascade under stressed conditions.