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Page 402 Saneto. J Transl Genet Genom 2020;4:384-428 I http://dx.doi.org/10.20517/jtgg.2020.40

Mitochondrial protein import and processing
Import
There are only 13 proteins produced by the mitochondrial genome. With the estimated 1500 proteins
needed for organelle structure and function, specialized protein import systems have evolved to get specific
mitochondrial proteins to their sub-organelle location. A full description of the import systems is beyond
the scope of this paper but was recently reviewed by Pfanner et al. [194] . Briefly, approximately 60% of the
nuclear-encoded proteins possess specific targeting signals that direct gene products from the cytosol to
the mitochondrial surface receptors and subsequently into mitochondrial subcompartments. Precursor
proteins are synthesized with a targeting N-terminal positively charged presequence. These proteins pass
from specific OMM translocase of the outer membrane (TOM) complex to a presequence translocase of
the inner membrane (TIM) complexes, TIM23 and TIM22. The protein then passes into the matrix by
the presequence translocase-associated motor. Nontargeted containing proteins use the TOM channel for
translocation, although the mode of delivery is likely different and depends on internal targeting signals.
There are small TIM chaperones of the intermembrane space that guide these complexes to the translocated
of the inner membrane (TIM22 complex). Many of these proteins contain cysteine motifs that are needed
for translocase.

Pathological variants in acylglycerol kinase (AGK) induce Senger syndrome, which is a rare recessive
disorder characterized by lactic acidosis, hypertrophic cardiomyopathy, and bilateral cataracts. AGK is a
component of the TIM22 complex and is essential for import and assembly of metabolite carrier proteins
in a kinase-independent manner [195] . A component of the TIM23 complex, TIMM50, is essential for
importing proteins into the inner compartment [196] . The transporter TIMM8A is part of a complex of TIM
proteins that facilitate the import of proteins across the inner membrane space by acting as a chaperone
to keep the hypdrophobic substrate unfolded [197,198] . TIMM8A is an X-linked gene that is associated with
deafness, dystonia, optic neuronopathy, and Mohr-Tranebjaerg syndrome. The X-linked AIFM1 gene
encodes a multifunctional protein, a mitochondrial apoptosis-inducing factor, which is a FAD-containing
and NADH-specific oxidoreductase. The AIFM1 protein is important for energy metabolism and involved
in the caspase-independent cell death pathway. In the inter-mitochondrial space, it contributes to folding
of some of the ETC subunits. Depending on genetic changes, AFIM1-induced disease can range from
infantile onset of severe neurodegeneration to a slowly progressive disorder [199] . The gene product of
DNAJC19 is complexed with another set of proteins, prohibitins, that form protein and lipid scaffolds in the
inner mitochondrial membrane. DNAJC19 complex is also involved in protein translocation [200] . The exact
role of DNAJC19 is not fully characterized in humans, but pathological variants have been found to induce
a phenotype of cardiomyopathy and ataxia, similar to Barth syndrome [201] . The GFER-encoded protein
is essential for disulfide protein folding in the intermitochondrial space. Variants induce an infantile
onset congenital cataract, sensorineural hearing loss, and developmental delay with multiple mtDNA
deletions [202] . MIPEP encodes a peptidase that is required for secondary processing within the matrix.
Variants in this gene has been found in patients with cardiomyopathy, developmental delay, seizures, and
early death [203] . PMPCA encodes the alpha subunit of the mitochondrial precursor peptidase, the primary
[204]
enzyme responsible for the maturation of most of the nuclear-encoded proteins entering into the matrix .
Phenotypically, patients with variants have a non-progressive cerebellar ataxia.

Processing
As would be expected in a highly coordinated quality control system involving transport across two
membranes and intramembrane space, errors are common. In addition, proteins are modified within the
matrix compartment for functionality. The mitochondrial protease system has evolved to prune abnormal
proteins and preserve functional integrity. There are three different classes, namely cysteine proteases,
metalloproteases, and serine proteases: whose functions are to remove import signals, degradation of
[205]
misfolded and damaged proteins, and determine half-life of short-lived regulatory proteins . There are