REVIEW
◥MITOCHONDRIA
Mitochondria—Striking a balance
between host and endosymbiont
Richard J. Youle*
Mitochondria are organelles with their own genome that arose froma-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.
O
ne challenge for eukaryotes centers around
the coordination of gene expression from
multiple distinct genomes ( 1 , 2 ). Although
most of the protein-coding genes from the
a-proteobacterial ancestors of mitochon-
dria have been lost or migrated into the nuclear
genome, a few remain along with genes for tRNAs
and ribosomal RNAs requiredfororganellartrans-
lation of the remaining protein-coding genes.
Mitochondria contain large, multisubunit protein
complexes involved in electron transport and aden-
osine 5′-triphosphate (ATP) synthesis that, ances-
trally,wereentirelyencodedintheendosymbiont
genome, which are now encoded partly in the
nuclear and partly in the organellar DNA. In
addition to the inherent difficulty in coordinating
gene expression between two genomes in different
compartments, the large excess of mitochondrial
genomes relative to the diploid nuclear genome
in each cell (on the order of 1000:1 in most mam-
malian cells) adds to potential error in producing
the proper stoichiometry of nuclear and mitochon-
drial encoded protein subunits. Thus, imprecision
in coordinating expression between the nuclear
and organelle genomes promotes incorrect stoi-
chiometries of the subunits in protein complexes
and invokes proteotoxic stress. Balancing sub-
unit stoichiometry is dealt with by coordinating
RNA transcription in the nucleus with protein
translation in the mitochondrial matrix and by
degrading extraneous protein subunits.
Another problem, at least for metazoan animals,
is that their innate immune response pathways
may recognize bacterially derived mitochondrial
components as pathogen-associated molecular
patterns (PAMPs) and generate inflammatory re-
sponses ( 3 , 4 ). Careful segregation of mitochon-
drial PAMPs from innate immune sensors within
the cytosol and on cell surfaces and efficient dis-
posal of damaged mitochondria are required to
avoid autoinflammation.
Exacerbating the potential threats of proteo-
toxic stress and PAMP release to innate immune
effectors, mitochondria are the center of the con-
trolled burn of nutrients to carbon dioxide and
water, generating ATP ( 5 ). Electrons from reduced
nicotinamide adenine dinucleotide and flavin
adenine dinucleotide, tunneling through inner
mitochondrial membrane transport complexes
to reduce molecular oxygen to water, occasionally
escape and generate oxyradicals that can oxidize
lipids and proteins in the mitochondrial mem-branes, especially those proximal to the electron
transport channels. Thus, oxidative damage adds
further demand for mitochondrial quality control
mechanisms.
Mitochondrial DNA (mtDNA) is also subject
to oxidative damage, mutations, and deletions.
Within individual human cells, hundreds to
thousands of mitochondrial genomes are packaged
into nucleoids within the matrix compartment,
surrounded by the inner and outer mitochondrial
membranes (Fig. 1). In contrast to the one or two
copies of the nuclear DNA that reproduces in
mammals through sexual admixture of two parents’
genomes and can recombine to mitigate mutation
accumulation, mitochondria reproduce asexually.
In contrast to bacteria, which can conjugate to
exchange DNA and allow mutation removal,
mitochondria in mammals are not known to do this
with any efficiency. Thus, the largely clonal expan-
sion of mtDNA carries the risk of mutational
meltdown, which is known as Muller’s ratchet,
with scant mechanisms to revert mutations to
wild-type sequences. The meltdown problem is
exacerbated because mtDNA has higher DNA
mutation rates than that of nuclear DNA owing
to greater replication rates yielding inherent errors,
as well as the proximity of mtDNA to electron
transport-generated oxyradicals, which can lead
to DNA mutations. Mitochondrial genomes are
invariably passed down essentially uniparentally-
maternally in mammals—presumably, to avoid
competition among genetically variant mitochon-
dria or more direct deleterious consequences of
two distinct mtDNA genomes occupying the
same cytoplasm, which is known as heteroplasmy
( 6 ). Although it is clear that the ontogeny of
the female germ line selects the least mutated
mitochondria for transmission to the next gen-
eration ( 7 – 9 ), it is less certain whether some
processes, such as apoptosis or autophagy, which
can eliminate damaged cells and mitochondria,RESEARCH
Youle,Science 365 , eaaw9855 (2019) 16 August 2019 1of7
Surgical Neurology Branch, National Institute of Neurological
Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
*Corresponding author. Email: [email protected]
Inner membraneIntermembrane spaceMatrixOuter membraneCis1 Msp1TOMTIMUbx2AFG3L2 Lon
YME1NNNCCCCdc48Fig. 1. The mitochondria has several distinct compartments that require distinct protein
quality control processes.Mitochondria have an inner membrane that contains the electron
transport machinery surrounding the Matrix compartment, which houses TCA cycle enzymes and
the mtDNA. An outer membrane surrounds the intermembrane space. TOM and TIM import
complexes transport proteins through the outer and inner membranes, respectively. Proteotoxic
stress is mitigated by AAA proteases LON, YME1, and AFG3L2/SPG7 that degrade misfolded
and superfluous proteins. The AAA ATPases p97/Cdc48 and ATAD1/Msp1 extract mislocalized
proteins from the outer mitochondrial membrane and clogged import channels.