Mitochondria—Striking a balance between host and endosymbiont

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Science  16 Aug 2019:
Vol. 365, Issue 6454, eaaw9855
DOI: 10.1126/science.aaw9855

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Putting a price on the powerhouse

Mitochondria—the so-called powerhouse of the cell—are derived from bacterial endosymbionts. This history provides opportunities and challenges for their host cells, particularly metazoans, including humans. Youle reviews the interplay between host and mitochondrial biology and highlights how mitochondrial ancestry has influenced innate immune responses. Keeping mitochondria both healthy and in check is key to organismal health and, when perturbed, leads to a variety of pathologies, including Parkinson's disease and inflammation.

Science, this issue p. eaaw9855

Structured Abstract


Evolution generally trundles along by selecting for mutations or by leveraging the new realms generated from chromosomal amplifications and the transfer of genes between organisms through vectors such as viruses. However, a few times 1 billion to 2 billion years ago, endosymbiosis between bacteria and Archaea yielded relatively huge bursts of divergent gene transfers, leading to the fungi, plants, and animals that we have today. One obvious benefit of endosymbiosis for Eukaryota centers on energy production. Mitochondria derived from α-proteobacteria efficiently generate adenosine triphosphate (ATP) from reduced carbon sources. Mitochondria also perform numerous key metabolic reactions and synthesize essential iron-sulfur compounds that serve as enzyme cofactors. Although most α-proteobacterial genes have transfered to the eukaryotic nucleus, mitochondria retain their own genome encoding for the ribosomal and transfer RNAs needed for the translation of the few protein-coding genes retained in their DNA. Although endosymbiosis offers tremendous evolutionary opportunities, mitochondria, particularly in animals, have some downsides. Here, I describe some of the drawbacks of mitochondria and the patches that metazoans have developed to resolve them.


Mitochondrial electron transport complexes involved in oxidative phosphorylation are composed of proteins encoded in both the mitochondrial and nuclear genomes. How these genomes coordinate the expression levels of their respective proteins has been recently deciphered. The newest advances reveal previously unknown pathways of mitochondria quality control—including nuclear genome RNA synthesis regulation, mitochondrial encoded protein synthesis control, regulated proteolysis, and selective autophagy—that deal with the challenges of the second genome of mitochondria in our cells. Animals have also developed ways to eliminate mutant mitochondrial DNA (mtDNA) and assure that progeny have a single, homoplasmic, and functional mitochondrial genome. Another emerging issue for mammals is that mitochondrial stress or failure of quality control processes can trigger inflammation. Mitochondria are involved in innate immunity at many levels, from mitochondrial antiviral signaling (MAVS) signaling of interferon-β production, to damage-associated molecular pattern (DAMP) release triggering unwanted inflammation, to mitigating virus spread through apoptosis of infected cells. Programmed cell death involves a pathway using mitochondria as a trigger for apoptosis, which resembles an inflammatory response.


Understanding how cells and tissues handle the problems of endosymbiosis enhances our understanding of disease etiology. When mitochondria experience inordinate stress or when quality control processes fail, cell-, tissue-, and even organism-wide responses are enacted. Mitochondrial dysfunction contributes to metabolic and neurological disorders. For example, people who lack a form of mitochondrial protein quality control develop ataxia, and those who lack compartmental quality control may develop Parkinson’s disease. Although debated, accumulation of mutations and deletions in mitochondrial DNA may be a key aspect of age-associated animal decline. Mitochondria also require careful maintenance because they share molecular patterns with bacteria and viruses that may activate innate immune pathways and inadvertently contribute to inflammatory disorders. An increasing number of human disease etiologies can be attributed to a wide range of mitochondrial defects, and efforts to treat mitochondrial disorders are advancing rapidly.

Mitochondria (magenta) in a single cell surround the nucleus (blue).

Mitochondria adopt divergent morphologies in different tissues and frequently fuse and divide. They have an outer membrane that surrounds an inner membrane, which houses the electron transport and ATP-synthesizing machinery. In one cell, there are hundreds to thousands of mitochondrial genomes packaged in nucleoids (green) dispersed throughout the organelle network that coordinate expression of proteins with the nuclear genome. Mitochondria were stained with antibody to Tom20, the nucleus was stained with 4′,6-diamidino-2-phenylindole, and nucleoids were stained with antibodies to transcription factor A, mitochondrial.


Mitochondria are organelles with their own genome that arose from α-proteobacteria living within single-celled Archaea more than a billion years ago. This step of endosymbiosis offered tremendous opportunities for energy production and metabolism and allowed the evolution of fungi, plants, and animals. However, less appreciated are the downsides of this endosymbiosis. Coordinating gene expression between the mitochondrial genomes and the nuclear genome is imprecise and can lead to proteotoxic stress. The clonal reproduction of mitochondrial DNA requires workarounds to avoid mutational meltdown. In metazoans that developed innate immune pathways to thwart bacterial and viral infections, mitochondrial components can cross-react with pathogen sensors and invoke inflammation. Here, I focus on the numerous and elegant quality control processes that compensate for or mitigate these challenges of endosymbiosis.

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