Socialized mitochondria: mitonuclear crosstalk in stress

Abstract

Traditionally, mitochondria are considered sites of energy production. However, recent studies have suggested that mitochondria are signaling organelles that are involved in intracellular interactions with other organelles. Remarkably, stressed mitochondria appear to induce a beneficial response that restores mitochondrial function and cellular homeostasis. These mitochondrial stress-centered signaling pathways have been rapidly elucidated in multiple organisms. In this review, we examine current perspectives on how mitochondria communicate with the rest of the cell, highlighting mitochondria-to-nucleus (mitonuclear) communication under various stresses. Our understanding of mitochondria as signaling organelles may provide new insights into disease susceptibility and lifespan extension.

Fig. 1. Proposed scenarios for the origin of eukaryotes and their mitochondria.

The evolutionary models for the endosymbiotic origin of mitochondria are generally classified as ‘mitochondria-early’ and ‘mitochondria-late’ scenarios depending on the timing of mitochondrial endosymbiosis during the process of eukaryogenesis. The ‘mitochondria-early’ model assumes metabolic symbiosis between prokaryotic archaea and α-proteobacteria. In this scenario, mitochondria were the first complex feature acquired within eukaryotic cells. In contrast, the ‘mitochondria-late’ hypothesis purports amitochondriate eukaryotes as the host engulfing mitochondrial ancestor. In this scenario, hosts with some eukaryotic features, referred to as ‘proto-eukaryotes’, engulf bacterial endosymbionts that become mitochondria. Both models include extensive gene transfer from the α-proteobacterium to the host and the coevolution of organellar and endosymbiont genomes in the host-endosymbiont complex. The figures were modified from ref. .

Fig. 2. Signaling messengers from the mitochondria that communicate stress to the nucleus.

a Stressed mitochondria can transport signaling molecules to the nucleus, where they either directly or indirectly regulate the expression of nuclear genes to trigger an adaptive stress response. b In the fed state, mitochondrial acetyl-CoA is delivered into the nucleus and utilized for histone acetylation in the nucleus for cell growth and proliferation. Stresses, including electron transport chain (ETC) dysfunction and nutrient stress, reduce the level of nucleocytosolic acetyl-CoA and limit histone acetylation. Such alterations in acetyl-CoA availability subsequently result in the induction of autophagy and promote survival under stress. c Mitochondrial stress generates reactive oxygen species (ROS) within the mitochondria. Mitochondrial ROS can trigger transcription-activating signaling cascades through redox-dependent modifications of proteins either directly or indirectly by activating ROS sensors. These ROS-activating signaling pathways lead to the expression of genes that mediate the adaptive response in the nucleus. d Calcium ions (Ca²⁺) can be released from mitochondria in response to many mitochondrial stresses, including depolarization of the mitochondrial membrane potential. Released Ca²⁺ triggers many different cellular pathways to stimulate transcription factors through Ca²⁺-sensitive protein kinases, phosphatases, and transcriptional repressors. Ca²⁺ signaling controls gene transcription to improve calcium homeostasis and mitochondrial metabolism. e The mitochondrial unfolded protein response (UPR^mt) is a protective transcriptional response that enhances the expression of genes involved in the mitochondrial protein quality control system and stress defense. Various mitochondrial insults, including mitochondrial proteotaxic stresses and mitonuclear imbalance, which is an imbalance between the mitochondrial proteins encoded by the nucleus and those that are mitochondrially encoded, can trigger the UPR^mt through a pleiotropic retrograde response to restore mitochondrial homeostasis. f The integrated stress response (ISR) is an adaptive stress pathway that is interconnected with various pathways under different stresses. Under diverse stress conditions, several kinases, including HRIs, are activated. These signals converge to phosphorylate the translation initiation factor eIF2α. The phosphorylation of eIF2α induces both general inhibition of protein translation and selective activation of a set of mRNAs that possess uORFs, such as ATF4. ATF4 in the nucleus binds to a transcription factor to activate genes involved in stress adaptation and mitochondrial function. eIF2α, α-subunit of eukaryotic initiation factor 2; ATF4, activating transcription factor 4.

Fig. 3. Schematic representation of mitochondria-derived peptides.

Mitochondria-derived peptides (MDPs) are a class of putative sORF-encoded polypeptides (SEPs) that are encoded within the mitochondrial ribosomal RNA (rRNA) region and have regulatory functions. The MDPs include humanin and SHLPs encoded by sORFs within the 16S rRNA and MOTS-c from the 12S rRNA region of the mitochondrial genome. MOTS-c, mitochondrial open reading frame of 12S rRNA-c; SHLPs, small humanin-like peptides.

Fig. 4. A mitochondrion-encoded messenger communicates stress signals to the nucleus.

Mitochondrial MOTS-c can trigger mitochondria-to-nucleus signaling. MOTS-c, under stress conditions, is released from the mitochondria and translocated to the nucleus. The MOTS-c-activated signaling cascade can induce the expression of protective genes in a redox-dependent manner. MOTS-c, mitochondrial open reading frame of 12S rRNA-c.