Mitochondria form contact sites with the nucleus to couple prosurvival retrograde response

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 dysfunction. MRR results in the nuclear stabilization of prosurvival transcription factors such as the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Here, we demonstrate that MRR is facilitated by contact sites between mitochondria and the nucleus. The translocator protein (TSPO) by preventing the mitophagy-mediated segregation o mitochonria is required for this interaction. The complex formed by TSPO with the protein kinase A (PKA), via the A-kinase anchoring protein acyl-CoA binding domain containing 3 (ACBD3), established the tethering. The latter allows for cholesterol redistribution of cholesterol in the nucleus to sustain the prosurvival response by blocking NF-κB deacetylation. This work proposes a previously unidentified paradigm in MRR: the formation of contact sites between mitochondria and nucleus to aid communication.

Restructured mitochondrial-nuclear interaction inPlasmodium falciparumdormancy and persister survival after artemisinin exposure

“…The same DegP2 ortholog was identified in a genetic screen: its disruption in T. gondii facilitated survival to lethal concentrations of DHA and its deletion in P. falciparum resulted in higher survival in the RSA (44). Interestingly, in breast cancer cells and mouse embryonic fibroblasts the responses to mitochondrial stress include formation of tethers between nuclei and mitochondria, coined Nuclear Associated Mitochondria (NAM) (45). ROS production after exposure of THP-1 derived macrophages to the fungal toxin altertoxin II was followed by relocation of mitochondria to perinuclear regions (46).…”

“…Mitochondrial retrograde response (MRR) signaling provides communications from mitochondria to nuclei that promote cellular adaptations under conditions of stress (47). Contact microdomains between the two organelles involve cholesterol redistribution and may promote a survival response in breast cancer (45). The MRR pathway is conserved among species, as exemplified by nuclear protein CLK-1 in Caenorhabditis elegans and its homolog in human cells COQ7, which serves as a regulator of this pathway limiting ROS production (48).…”

TSPO protein binding partners in bacteria, animals, and plants

“…A similar difference in location relative to proliferation was reported for liver tumor and breast cancer cells (Hardwick et al 1999 ; Corsi et al 2005 ). There is evidence that TSPO may localize to mitochondria-associated membranes (MAMs), zones where the endoplasmic reticulum (ER) contacts the OMM (McEnery et al 1992 ; Gatliff et al 2014 ; Zhou et al 2015 ; Loth et al 2020 ); to nucleus-associated mitochondria (NAMs) where mitochondrial and nuclear membranes meet (Desai et al 2020 ); and to contact regions between the OMM and the inner mitochondrial membrane (IMM) (Lacapere and Papadopoulos 2003 ; Liu et al 2006 ; Papadopoulos et al 2006 ; Rone et al 2012 ; Guilarte et al 2016 ). Such contacts expand the range of possible binding partners for TSPO.…”

“…ACBD3 is upregulated by photodynamic therapy, which is possibly mediated by its interaction with TSPO (Fan et al 2010 ). A newly-reported interaction, nucleus-associated mitochondria (NAM), has been identified as part of a mitochondrial retrograde signaling pathway in response to the mitochondrial stressor staurosporine, in which a complex of TSPO, PKA, ACBD3, and AKAP95 was required to tether mitochondria to the nucleus (Desai et al 2020 ). ACBD3 contains an acyl-CoA binding motif similar to the one identified in the diazepam binding inhibitor (DBI; see below), suggesting they could share a common site of interaction with TSPO (Lacapere and Papadopoulos 2003 ; Liu et al 2003 ; Rone et al 2009 ).…”

The Causal Role of Lipoxidative Damage in Mitochondrial Bioenergetic Dysfunction Linked to Alzheimer’s Disease Pathology

“…Other critical cellular processes in which mitochondria are also involved include biosynthesis of lipids, iron-sulfur clusters, heme groups, presynaptic neurotransmitters, calcium homeostasis, and cell death, among others [ 24 ]. To accomplish this diversity of functions, mitochondria show a great dynamism and establish a coordinated network and crosstalk among themselves and with other cell organelles including, for instance, endoplasmic reticulum and nucleus, in order to adapt their response to a continuously changing microenvironment under physiological and pathological conditions [ 25 , 26 , 27 ].…”