Retrograde signalling pathways and mitochondrial dysfunction

Retrograde signalling pathways and mitochondrial dysfunction

Using those models, we have discovered a new retrograde signalling pathway, through which mitochondrial dysfunction regulates the expression of nuclear genes. This mitochondria-to-nucleus communication triggers an increase in cytosolic calcium, activates calmoduline kinase IV (CaMKIV) and the cAMP-Responsive Element Binding protein (CREB) transcription factor (Arnould et al, EMBO J. 2002).

In mtDNA-depleted cells, it is intriguing to observe that this organelle is still actively generated, despite its absence of functionality (on the oxidative phosphorylation point of view). We thus studied two specific aspects of cells depleted of mtDNA: mitochondrial biogenesis and the mitochondrial membrane potential. We have shown that in mtDNA-depleted cells, mitochondria biogenesis depends on the Ca⁺⁺-CaMKIV-CREB pathway, and not on the transcription factors classically involved in mitochondrial biogenesis (NRF1, NRF2, PPAR or MEF2) (Mercy et al, FEBS J. 2005). Regarding the mitochondrial membrane potential of rho⁰ cells, it arises at least partly from the overexpression of the mitochondrial chloride channel (mtCLIC), induced by the transcription factors CREB and p53 (Arnould, FASEB J. 2003). Although the transcription factor CREB is induced by mitochondrial dysfunction, it is far from being the only retrograde signalling pathway in mammalian cells (reviewed in Renard et al, 2012). The transcription factor C/EBP homologous protein-10 (CHOP-10) is also activated in response to number of mitochondrial stresses, such as doxycycline, an inhibitor of mitochondrial translation, or mtDNA depletion, that induce CHOP-10, in an ATF-4-dependent manner (Michel et al, Mitochondrion 2015).

We currently investigate the possible participation of microRNAs to the retrograde communication (ongoing research, PhD thesis of Morgane CANONNE).