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  • Review Article
  • Published:

Mitonuclear communication in homeostasis and stress

Nature Reviews Molecular Cell Biology volume 17, pages 213–226 (2016)Cite this article

Subjects

Key Points

  • Mitochondria carry out crucial cellular functions such as energy harvesting. They possess their own genome, encoding 13 proteins, although most of the ∼1,200 mitochondrial proteins originate from the nucleus. Therefore, the nucleus and mitochondria have to constantly communicate to adjust their activities in order to ensure cellular homeostasis and adaptation to mitochondrial stress. This communication is defined as mitonuclear communication.

  • The nucleus modulates gene expression and mitochondrial function through anterograde regulation signalling. Conversely, mitochondria can elicit a retrograde response, on the basis of energetic cues, ROS or calcium signalling, that activates the expression of nuclear genes to respond and adapt to those cellular conditions.

  • Proteostatic stress in the mitochondria can initiate many feedback responses, such as the mitochondrial unfolded protein response (UPRmt), the proteolytic stress response and the heat shock response, which directly modulate nuclear gene expression and are involved in alleviating the stress.

  • In order to induce a more general adaptation to a cellular state, mitochondrial stress can trigger the integrated stress response (ISR), which reduces cytosolic protein synthesis globally and induces the expression of cellular stress response genes.

  • Mitochondrial stress can be signalled to other cells of the organism by extracellular cues, such as the so-called mitokines, to orchestrate the coordinated adaptation of the whole organism to stress.

  • Given their central role in cellular metabolism and in the maintenance of cellular homeostasis, mitochondria are closely involved in the ageing process. Therefore, several mitochondrial stress and mitonuclear communication pathways modulate lifespan across species.

Abstract

Mitochondria participate in crucial cellular processes such as energy harvesting and intermediate metabolism. Although mitochondria possess their own genome — a vestige of their bacterial origins and endosymbiotic evolution — most mitochondrial proteins are encoded in the nucleus. The expression of the mitochondrial proteome hence requires tight coordination between the two genomes to adapt mitochondrial function to the ever-changing cellular milieu. In this Review, we focus on the pathways that coordinate the communication between mitochondria and the nucleus during homeostasis and mitochondrial stress. These pathways include nucleus-to-mitochondria (anterograde) and mitochondria-to-nucleus (retrograde) communication, mitonuclear feedback signalling and proteostasis regulation, the integrated stress response and non-cell-autonomous communication. We discuss how mitonuclear communication safeguards cellular and organismal fitness and regulates lifespan.

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Figure 1: Mitonuclear communication.
Figure 2: Anterograde regulation.
Figure 3: The retrograde response.
Figure 4: Mitonuclear feedback.
Figure 5: The integrated stress response.

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Acknowledgements

The authors thank all members of the Auwerx laboratory for their helpful comments on the manuscript and apologize for the omission of relevant work owing to space constraints. P.M.Q. is supported by a long-term fellowship from the European Molecular Biology Organization (EMBO; ALTF 480–2014). J.A. is the Nestlé Chair in Energy Metabolism, and the Auwerx laboratory is supported by grants from the École Polytechnique Fédérale de Lausanne, the Swiss National Science Foundation (31003A-140780), the AgingX programme of the Swiss Initiative for Systems Biology (51RTP0-151019), the Krebsforschung Schweiz/Swiss Cancer League (KFS-3082-02-2013) and the US National Institutes of Health (NIH; R01AG043930).

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  1. Pedro M. Quirós and Adrienne Mottis: These authors contributed equally to this article.

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  1. Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, CH-1015, Switzerland

    Pedro M. Quirós, Adrienne Mottis & Johan Auwerx

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Glossary

Endosymbionts

Organisms that live within another organism in a symbiotic relationship.

Electron transport chain

(ETC). A group of protein complexes that pass electrons from one to another via redox reactions coupled with the transfer of protons across the inner mitochondrial membrane, creating a proton gradient that drives ATP synthesis.

Intermediate metabolism

The intermediate steps by which nutrient molecules or foodstuffs are metabolized intracellularly.

Calcium buffering

A mechanism that regulates calcium ion (Ca2+) concentrations within the cytoplasm.

Oxidative phosphorylation

(OXPHOS). A biochemical pathway within mitochondria that generates ATP through the oxidation of nutrients.

Nuclear receptors

Ligand-dependent transcription factors that are characterized by a central DNA-binding domain and a carboxy-terminal ligand-binding domain.

Metabolic reprogramming

The set of changes in cellular metabolism that allow quiescent cells to proliferate; it is considered to be a hallmark of cancer.

Reactive oxygen species

(ROS). Reactive molecules generated in cells by the reduction of oxygen with a single electron (superoxide), two electrons (hydrogen peroxide) or three electrons (hydroxyl radical).

Anaplerotic reactions

Reactions that replenish intermediates of metabolic pathways.

Glyoxylate cycle

An anabolic pathway, and a variation of the tricarboxylic acid cycle, that converts two acetyl-CoA molecules to dicarboxylic acid (succinate); this cycle is not present in mammals.

Mitophagy

A selective form of autophagy that is responsible for the elimination of defective mitochondria.

Ionophores

Molecules that bind to ions and allow their passage across a membrane or a lipophilic phase.

Mitochondrial membrane potential

An electrochemical potential formed by chemiosmosis that results from the proton gradient generated across the inner mitochondrial membrane by the mitochondrial respiratory chain.

Mitochondria fuel switching

Adaptations in mitochondrial function and electron transport chain organization as a result of changes in the availability of the fuel source.

Mitochondrial uncoupling

The dissociation of mitochondrial respiration from ATP generation, characterized by increased permeability of the inner mitochondrial membrane to protons and subsequent dissipation of mitochondrial membrane potential.

Mitonuclear imbalance

Mitonuclear imbalance occurs when oxidative phosphorylation subunits encoded by both mitochondrial and nuclear DNA fail to assemble together in precise stoichiometric ratios to ensure proper mitochondrial function, owing to an increase or decrease of subunits from one of the origins.

Mitohormesis

A process in which low levels of mitochondrial stress cause a protective cellular response that reduces susceptibility to disease and potentially promotes longevity.

Mitofusins

High-molecular-mass GTPases that are essential for mitochondrial fusion.

Mouse BXD genetic reference population

A family of recombinant inbred mouse strains, which is currently the largest and best-characterized mouse genetic reference population, composed of ∼160 lines.

Mitokines

Signals released from a cell or tissue in response to mitochondrial stress to modulate cellular or organismal homeostasis and longevity.

Ketogenesis

A metabolic pathway in the liver that generates ketones using acetyl-CoA, which provides an important fuel source for the brain and other tissues during long-term fasting.

Rho0 cells

Eukaryotic cells that lack mitochondrial DNA.

Formyl peptides

Small peptides in mitochondria and bacteria with a formylated amino-terminal Met and, usually, a hydrophobic amino acid at the carboxy-terminal.

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Quirós, P., Mottis, A. & Auwerx, J. Mitonuclear communication in homeostasis and stress. Nat Rev Mol Cell Biol 17, 213–226 (2016). https://doi.org/10.1038/nrm.2016.23

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