Mitochondria form contact sites with the nucleus to couple pro-survival retrograde response

Desai, R and East, D A and Hardy, L and Crosby, J and Rigon, M and Faccenda, D and Alvarez, M S and Singh, A and Mainenti, M and Hussey, L K and Bentham, R and Szabadkai, G and Zappulli, V and Dhoot, G and Romano, L E and Dong, X and Coppens, I and Hamacher-Brady, A and Chapple, J P and Abeti, R and Fleck, R A and Vizcay-Barrena, G and Smith, K and Campanella, M (2020) Mitochondria form contact sites with the nucleus to couple pro-survival retrograde response. Science Advances.

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Official URL: https://advances.sciencemag.org/content/6/51/eabc9...

Abstract

Mitochondria drive cellular adaptation to stress by retro-communicating with the nucleus. This process is known as Mitochondrial Retrograde Response (MRR) and is induced by mitochondrial dysfunctions. MRR results in the nuclear stabilization of pro-survival transcription factors such as the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). Here we demonstrate that MRR is facilitated by contact sites between mitochondria and the nucleus. The 18kD Translocator Protein (TSPO), which de-ubiquitylates and stabilizes the mitochondria thereby preventing their mitophagy-mediated segregation, is required for this interaction. The tethering TSPO enacts is mediated by the complex formed with the Protein kinase A (PKA) via the A-kinase anchoring protein Acyl-CoA Binding Domain Containing 3 (ACBD3) and allows the redistribution of cholesterol which sustains the pro-survival response by blocking NF-kB de-acetylation. This work proposes a new paradigm in the mitochondrial retro-communication by revealing the existence of contact sites between mitochondria and the nucleus and a signalling role for cholesterol.

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