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Page 72 Webb et al. J Transl Genet Genom 2020;4:71-80 I https://doi.org/10.20517/jtgg.2020.11

Complexes I, III, IV, and V; 22 which encode mitochondrial tRNAs; and 2 which encode mitochondrial
rRNAs. By far the majority of mitochondrial proteins are produced on cytosolic ribosomes and are
transported to the mitochondria as precursors via the translocase of the mitochondrial outer membrane
(TOM complex), the presequence translocase (TIM23 complex), and presequence-translocase-associated
[2]
motor located at the inner mitochondrial membrane .

Oxidative phosphorylation and generation of cellular ATP requires coordinated biogenesis and assembly
of respiratory chain complexes at the inner mitochondrial membrane. Electrons are transferred along the
respiratory chain complexes from the reducing equivalents NADH and FADH2 to oxygen to produce water
and generate a proton gradient across the inner membrane. This proton gradient enables ATP synthase to
generate ATP from ADP and phosphate. In humans, five multi-subunit protein complexes compose the
respiratory chain and oxidative phosphorylation system: NADH dehydrogenase (Complex I); succinate
dehydrogenase (Complex II); coenzyme Q: cytochrome c-oxidoreductase (Complex III); cytochrome c
oxidase (Complex IV); and ATP synthase (Complex V). Complex II is composed of proteins encoded
entirely by the nuclear genome, whereas the remaining complexes have protein subunit components encoded
by both nuclear and mitochondrial genomes. Additionally, complex assembly is a highly coordinated process
involving a number of assembly factors, as well as coordination of nuclear and mitochondrial genes. Defects
in mitochondrial translation processes may result in impaired activities of these complexes, resulting in
[3]
deficient aerobic energy metabolism and clinical disease in humans .
Mitochondrial translation is specifically defined as the process within mitochondria whereby mitochondrial
mRNA (mt-mRNA) is translated by mitochondrial ribosomes (mitoribosomes) to generate an amino acid
polypeptide. Mitochondrial translation is necessary for the generation of thirteen respiratory complex
subunits. mt-mRNAs are unique in that they are uncapped, have no or very few 5’-untranslated nucleotides,
[4]
and contain a poly A tail that immediately follows or forms part of the stop codon . The mitoribosome
translates the mt-mRNA by inducing the binding of complementary tRNA anticodon sequences to mt-mRNA
codons in a manner analogous to that performed by cytoplasmic ribosomes. The tRNAs carry specific
amino acids that are linked together into a polypeptide as the mt-mRNA passes through and is read by the
mitoribosome. Mitoribosomes have a higher protein:RNA ratio (2:1 vs. 1:2 in cytoplasmic ribosomes) and
[5]
are less dense (55S vs. 80S) than cytoplasmic ribosomes . Additionally, mitoribosomal translation is unique
in that there are several differences from the universal genetic code. Human mitochondria translate the
conventional UGA stop codon as tryptophan, reprogram the two conventional arginine codons AGA and
[6]
AGG for termination, and code the conventional isoleucine AUA codon as methionine .

Structural studies have established that many mitochondrial ribosome proteins have eubacterial orthologs,
but there also exist additional proteins without such orthologs. Mitoriboproteins have traditionally been
named by a MRPS (Mitochondrial Ribosomal Protein Small subunit)/MRPL (Mitochondrial Ribosomal
[5]
Protein Large subunit) nomenclature . Recently, a new naming convention has been proposed based on
functional/structural relationships of mitoribosomal proteins across species in order to reduce ambiguity
[7]
arising from non-orthologous proteins from different species being assigned similar names .

Mitochondrial translation defects resulting in human disease may have varying organ involvement, varying
age of onset, and varying modes of inheritance. This specific class of mitochondrial disease may be caused
by the following mechanisms: mitochondrial tRNA mutations, mitochondrial aminoacyl-tRNA synthetase
mutations, mitochondrial rRNA mutations, and mitochondrial ribosomal protein mutations. Additional
mechanisms of abnormal mitochondrial translation exist, including impaired translation secondary to
mtDNA depletion and defects in mitochondrial RNA synthesis, modification, and degradation, which are
[8,9]
beyond the scope of this article but have been recently reviewed .