Page 175 - Read Online

Saneto. J Transl Genet Genom 2020;4:384-428 I http://dx.doi.org/10.20517/jtgg.2020.40 Page 403

at least 10 diseases associated with loss of protease function: eight are recessive (AFG3L2 CLPP, LONP1,
PARK7, PARL, SPG7, UQCRC2, and XPNPEP3), two are dominant (HTRA2, and IMMP2L0, and one has
both dominant and recessive modes of inheritance (AFG3L2).

Nonketotic hyperglycinemia (NKH) is an autosomal disorder characterized by variants in the glycine
cleavage system and lipoate synthase [206,207] . NKH due to variants in the lipoate synthetase are described
in the next section below on Iron Cluster Biosynthesis and Mitochondrial Iron Homeostasis. The glycine
cleavage system is composed of three enzymes, P, T, and L subunits, and one carrier protein, H subunit [208] .
The majority of disease-causing variants are in the pyridoxal phosphate-dependent glycine decarboxylase
encoded P subunit with the remaining in the amino methyltransferase encoded T subunit.

The process of fusion and fission, also named mitochondrial dynamics, in part monitors healthy and
impaired mitochondria in response to physiological signals and metabolic stress. Proteases play a role in
these processes. Damaged mitochondria undergo degradation by mitophagy [209] . PINK1 and PARKIN are
two proteins that mediate this autophagy process. PINK recruits PARKIN to damaged mitochondria and
the Presenilin Associated Rhomboid-Like (PARL) protease within the inner mitochondrial membrane
and induces mitophagy [210] . Rare recessive pathological variants in PARL results in PINK1 not being
cleaved during protein damage and results in accumulation of abnormal proteins with subsequent
incomplete mitophagy. The cascade of altered PARL function is associated with induction of Parkinson
disease [211] . XPNPEP3 is a protease thought to be involved in post-translation modifications of proteins
controlling their half-life [212] . Recessive pathological variants in XPNPEP3 give rise to a nephronophthisis-
like nephropathy [213] . Multiple etiologies of hereditary spastic paraplegia (SPG) exist. SPG type 7 is due
to alterations in paraplegin generating gene, SPG7 [214] . Other phenotypes of SPG7 variants induce CPEO,
optic atrophy, and muscle showing multiple mtDNA deletions [215] . Alterations in other essential proteases
can cause disease. Variants in PMPCB, which encodes the catalytic subunit of mitochondrial processing
protease, induce a progressive neurological disease in early childhood [216] . LonP1 is one of the members of
the highly conserved AAA+ superfamily of soluble proteases found in the matrix that selectively processes
a variety of proteins to both activate and degrade damage proteins. Recessive variants in the LONP1 gene
have been found to cause Leigh syndrome and the syndrome of cerebral, ocular, dental, auricular, and
skeletal anomalies [217,218] . Another of the matrix proteases, IMMP2L, is associated with removal of the
signal N-terminal peptide within proteins. Variants in IMMP2L have been associated with a small subset
of patients with Tourette syndrome with dominant inheritance [219] . The mitochondrial ATP-independent
serine protease HTRA2 resides in the intermembrane space and provides protein homeostasis, as well as is
involved in apoptosis. Recessive and dominant variants in HTRA2 induce disease ranging from infants to
adults. Adult onset has been associated with dominant HTRA2 variants inducing tremor, while recessive
variants cause adult onset Parkinson’s disease and infants with recessively inherited seizures, dysphagia,
hypotonia, apnea, and cataracts [220,221] . CLPP is an ATP-dependent matrix protease and is also involved
in ribosome assembly within the inner membrane. Variants in CLPP induce Perrault syndrome (type
3), which presents with sensorineural hearing loss and ovarian failure [222] . Several of the AAA proteases
lie within the inner membrane. When the catalyst domain lies facing the inner membrane space, it is
given the name of i-AAA, and when facing in the matrix m-AAA protease. The i-AAA protease YME1L
is involved with dynamics and metabolic integrity of the organelle [223] . Variants in YME1L alter OPA1
processing, which induces imbalance between fission and fusion with the phenotype of optic atrophy [224] .
Another member of the i-AAA proteases, AFG3L2, assembles into oligomeric isoenzymes or with SPG7
subunits. Variants in AFG3L2 produce dominant spinocerebellar ataxia and recessively inherited spastic-
neuropathy syndrome (SCA28), while SPG7 induces recessive inherited spastic paraplegia [225] . The m-AAA
ATPase, ATAD3A, lies in the IMM with contact sites with the OMM. The N-terminal domain interacts
with the inner surface of the OMM with the C-terminus ATPase domain in the matrix [226] . Alterations
in ATAC3A are involved in fission, mitochondrial fragmentation, cholesterol synthesis (a component of