Mitochondria Form Contact Sites with the Nucleus to Couple Pro-Survival Retrograde Response

Mitochondria drive cellular adaptation to stress by retro-communicating with the nucleus to promote cytoprotective mechanisms. This process of inter-organelles interplay is known as the Mitochondrial Retrograde Response (MRR) and is enacted by alterations in the mitochondrial function which result into the nuclear stabilization of transcription factors such as the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). Here, we demonstrate that this adaptive response is relying on the formation of contact sites between mitochondria and nucleus. These hot-spots of communication allow for the redistribution of cholesterol to the nucleus which favours nuclear residency and activity of the NF-kB. The expression level of the cholesterol Translocator Protein (TSPO), resident on the Outer Mitochondrial Membrane (OMM), is key to the formation of these contact sites and the implementation of the cytoprotective response. This work provides therefore a new paradigm in the intracellular communication during stress by reporting the first evidence for a functional and biochemical tethering between mitochondria and nucleus which governs cellular adaptation.