REVIEW SUMMARY
◥MITOCHONDRIA
Mitochondria—Striking a balance
between host and endosymbiont
Richard J. Youle*
BACKGROUND:Evolution generally trundles
along by selecting for mutations or by leverag-
ing the new realms generated from chromo-
somal 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 diver-
gent 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
froma-proteobacteria efficiently generate aden-
osine triphosphate (ATP) from reduced carbon
sources. Mitochondriaalso perform numerous
key metabolic reactions and synthesize essen-
tial iron-sulfur compounds that serve as enzyme
cofactors. Although mosta-proteobacterial
genes have transfered to the eukaryotic nucleus,
mitochondria retain their own genome encod-
ing for the ribosomal and transfer RNAs needed
for the translation of the few protein-coding
genes retained in their DNA. Although endo-
symbiosis offers tremendous evolutionary oppor-
tunities, 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.ADVANCES:Mitochondrial electron trans-
port complexes involved in oxidative phospho-
rylation 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 re-
cently deciphered. The newest advances reveal
previously unknown path-
ways of mitochondria
quality control—including
nuclear genome RNA syn-
thesis regulation, mito-
chondrial encoded protein
synthesis control, regu-
lated 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 func-
tional 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 mito-
chondrial antiviral signaling (MAVS) signaling
of interferon-bproduction, to damage-associated
molecular pattern (DAMP) release triggering un-
wanted inflammation, to mitigating virus spread
through apoptosis of infected cells. Programmed
cell death involves a pathway using mitochon-
dria as a trigger for apoptosis, which resembles
an inflammatory response.OUTLOOK:Understanding how cells and tis-
sues handle the problems of endosymbiosis en-
hances 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 meta-
bolic and neurological disorders. For example,
people who lack a form of mitochondrial pro-
tein 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 path-
ways and inadvertently contribute to inflam-
matory 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.▪RESEARCH
Youle,Science 365 , 655 (2019) 16 August 2019 1of1
Surgical Neurology Branch, National Institute of Neurological
Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
*Corresponding author. Email: [email protected]
Cite this article as R. Youle,Science 365 , eaaw9855
(2019). DOI: 10.1126/science.aaw9855Mitochondria (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.
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at http://dx.doi.
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science.aaw9855
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