Mitochondria to nucleus: Activate HIF1α

Abstract

Mitochondria communicate information about redox potential and bioenergetics status to the nucleus through a process called retrograde signaling. Cagin et al. investigated mitochondrial retrograde signaling using a Drosophila model with neuronal-specific mitochondrial dysfunction by inducing the overexpression of the mitochondrial transcription factor TFAM, which stimulates expression of mitochondrially encoded genes and functions in mitochondrial DNA replication. Overexpression of TFAM in motor neurons reduced adult lifespan and climbing ability and caused defective wing inflation. The number and gross morphology of motor neurons were not different in the TFAM-overexpressing flies compared with that in wild-type flies, but the number of sites of neurotransmitter release and mitochondria at the neuromuscular junction (NMJ) was reduced. Transcriptional microarray analysis of the larval central nervous tissue from flies overexpressing TFAM in all neurons showed that expression of 371 genes was significantly changed. Although, unsurprisingly, most of the affected transcripts were encoded by genes associated with the mitochondrial retrograde response, there was a significant overlap with genes regulated by hypoxia-inducible factor 1α (HIF1α). Indeed, manipulation of Sima, the Drosophila ortholog of HIF1α, abundance in the motor neuron–specific TFAM-overexpressing flies indicated the involvement of HIF1α in responding to compromised mitochondrial function. Although flies overexpressing both Sima and TFAM in motor neurons exhibited reduced climbing ability, flies overexpressing TFAM and Sima-targeted shRNA motor neurons exhibited improved climbing ability and wing inflation compared with the TFAM-overexpressing flies. Sima knockdown in motor neurons rescued the reduced life span of the motor neuron–specific TFAM-overexpressing flies and restored the number of sites of neurotransmitter release in the NMJ to those present in wild-type flies. In addition, Sima knockdown in Drosophila models of mitochondrial or Parkinson’s diseases rescued the phenotypes of defective wing inflation and reduced climbing ability. Thus, this study suggests mitochondrial retrograde signaling in neurons stimulates the hypoxic response, which contributes to impaired function of neurons with damaged or nonfunctional mitochondria.

U. Cagin, O. F. Duncan, A. P. Gatt, M. S. Dionne, S. T. Sweeney, J. M. Bateman, Mitochondrial retrograde signaling regulates neuronal function. Proc. Natl. Acad. Sci. U.S.A. 112, E6000–E6009 (2015). [PubMed]