Mitochondrial oxidative phosphorylation disorder

Summary

Mitochondrial oxidative phosphorylation disorder (MONDO:0016387) is a disease (an umbrella term covering 48 Mondo subtypes) caused by FARS2 (GenCC Strong), with 6 cohort genes.

At a glance

• Causal gene: FARS2 (GenCC Strong)
• Umbrella term: 48 Mondo subtypes
• Cohort genes: 6
• ClinVar variants: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial oxidative phosphorylation disorder
Mondo ID	MONDO:0016387
Orphanet	223713
ICD-11	1204111545
UMLS	C5679825
MedGen	1825947
GARD	0020546
Is cancer (heuristic)	no

Also known as: OXPHOS disease · OXPHOS system deficiency

Data availability: 5 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 48 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder

Related subtypes (13): oxoglutaricaciduria, multiple acyl-CoA dehydrogenase deficiency, inborn mitochondrial myopathy, HSD10 mitochondrial disease, histiocytoid cardiomyopathy, hypotonia-cystinuria syndrome, fumaric aciduria, 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, mitochondrial pyruvate carrier deficiency, mitochondrial membrane transport disorder, inherited lipoic acid biosynthesis defect, pyruvate dehydrogenase deficiency, OPA1-related optic atrophy with or without extraocular features

Subtypes (48): mitochondrial respiratory chain complex deficiency, combined oxidative phosphorylation deficiency, myopathy, lactic acidosis, and sideroblastic anemia, optic atrophy 3, autosomal dominant optic atrophy, classic form, Leigh syndrome, mitochondrial non-syndromic sensorineural hearing loss, maternally-inherited diabetes and deafness, chronic diarrhea with villous atrophy, Kearns-Sayre syndrome, Leber hereditary optic neuropathy, NARP syndrome, deafness, aminoglycoside-induced, hereditary spastic paraplegia 7, spinocerebellar ataxia type 28, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, spastic ataxia 3, pontocerebellar hypoplasia type 6, autosomal recessive optic atrophy, OPA7 type, acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins, congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome, spastic ataxia 4, hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome, hereditary spastic paraplegia 55, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, Charcot-Marie-Tooth disease recessive intermediate D, autosomal dominant mitochondrial myopathy with exercise intolerance, Charcot-Marie-Tooth disease type 4K, hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome, hereditary spastic paraplegia 77, fatal infantile encephalocardiomyopathy, FASTKD2-related infantile mitochondrial encephalomyopathy, autosomal dominant optic atrophy and peripheral neuropathy, ataxia neuropathy spectrum, maternally-inherited mitochondrial dystonia, Perrault syndrome, hypertrophic cardiomyopathy and renal tubular disease due to mitochondrial DNA mutation, adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy, mitochondrial DNA maintenance syndrome, coenzyme Q10 deficiency, mitochondrial DNA depletion syndrome, periodic paralysis with later-onset distal motor neuropathy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Zellweger-like syndrome without peroxisomal anomalies, maternally-inherited progressive external ophthalmoplegia, Leber plus disease, encephalopathy due to mitochondrial and peroxisomal fission defect, severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

5 retrieved; paginated sample, class counts are floors:

2 pathogenic/likely pathogenic, 1 pathogenic, 1 likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
506018	NM_139242.4(MTFMT):c.1100_1101del (p.Phe367fs)	MTFMT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
35496	NM_012123.4(MTO1):c.1282G>A (p.Ala428Thr)	MTO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
225255	NM_017909.4(RMND1):c.713A>G (p.Asn238Ser)	RMND1	Pathogenic	criteria provided, multiple submitters, no conflicts
505907	NM_032861.4(SERAC1):c.21C>A (p.Cys7Ter)	SERAC1	Likely pathogenic	criteria provided, single submitter
517222	NM_025152.3(NUBPL):c.2T>C (p.Met1Thr)	NUBPL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
FARS2	Strong	Autosomal recessive	combined oxidative phosphorylation defect type 14	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FARS2	Orphanet:319519	Combined oxidative phosphorylation defect type 14
FARS2	Orphanet:466722	Autosomal recessive spastic paraplegia type 77
MTO1	Orphanet:314637	Mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency
NUBPL	Orphanet:2609	Isolated complex I deficiency
SERAC1	Orphanet:352328	MEGDEL syndrome
RMND1	Orphanet:324535	Combined oxidative phosphorylation defect type 11
RMND1	Orphanet:642945	Perrault syndrome type 1
RMND1	Orphanet:642976	Perrault syndrome type 2
MTFMT	Orphanet:319524	Combined oxidative phosphorylation defect type 15

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FARS2	HGNC:21062	ENSG00000145982	O95363	Phenylalanine–tRNA ligase, mitochondrial	gencc
MTO1	HGNC:19261	ENSG00000135297	Q9Y2Z2	5-taurinomethyluridine-[tRNA] synthase subunit MTO1, mitochondrial	clinvar
NUBPL	HGNC:20278	ENSG00000151413	Q8TB37	Iron-sulfur cluster transfer protein NUBPL	clinvar
SERAC1	HGNC:21061	ENSG00000122335	Q96JX3	Protein SERAC1	clinvar
RMND1	HGNC:21176	ENSG00000155906	Q9NWS8	Required for meiotic nuclear division protein 1 homolog	clinvar
MTFMT	HGNC:29666	ENSG00000103707	Q96DP5	Methionyl-tRNA formyltransferase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FARS2	Phenylalanine–tRNA ligase, mitochondrial	Is responsible for the charging of tRNA(Phe) with phenylalanine in mitochondrial translation.
MTO1	5-taurinomethyluridine-[tRNA] synthase subunit MTO1, mitochondrial	Component of the GTPBP3-MTO1 complex that catalyzes the 5-taurinomethyluridine (taum(5)U) modification at the 34th wobble position (U34) of mitochondrial tRNAs (mt-tRNAs), which plays a role in mt-tRNA decoding and mitochondrial translatio…
NUBPL	Iron-sulfur cluster transfer protein NUBPL	Iron-sulfur cluster transfer protein involved in the assembly of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I).
SERAC1	Protein SERAC1	Facilitates the transport of serine from the cytosol to the mitochondria by interacting with and stabilizing Sideroflexin-1 (SFXN1), a mitochondrial serine transporter, playing a fundamental role in the one-carbon cycle responsible for the…
RMND1	Required for meiotic nuclear division protein 1 homolog	Required for mitochondrial translation, possibly by coordinating the assembly or maintenance of the mitochondrial ribosome.
MTFMT	Methionyl-tRNA formyltransferase, mitochondrial	Methionyl-tRNA formyltransferase that formylates methionyl-tRNA in mitochondria and is crucial for translation initiation.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	2	4.0×	0.166
Other/Unknown	4	1.2×	0.458

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FARS2	Enzyme (other)	yes	6.1.1.20	Phenylalanyl-tRNA_Synthase, Phe-tRNA-synth_IIc_mito, Fdx_antiC-bd
MTO1	Other/Unknown	no		MnmG-rel, MnmG-rel_CS, MnmG_C
NUBPL	Other/Unknown	no		Mrp-like_CS, Mrp/NBP35_ATP-bd, P-loop_NTPase
SERAC1	Other/Unknown	no		ARM-like, ARM-type_fold, AB_hydrolase_fold
RMND1	Other/Unknown	no		DUF155, RMD1/Sad1-interacting
MTFMT	Enzyme (other)	yes	2.1.2.9	Formyl_transf_N, Formyl_trans_C, Fmt

Expression context

Cohort genes with no expression data: 0.

6 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endothelial cell	3
calcaneal tendon	2
gluteal muscle	1
triceps brachii	1
germinal epithelium of ovary	1
sperm	1
adrenal tissue	1
skeletal muscle tissue of biceps brachii	1
epithelial cell of pancreas	1
islet of Langerhans	1
ganglionic eminence	1
primordial germ cell in gonad	1
buccal mucosa cell	1
cardiac muscle of right atrium	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FARS2	260	ubiquitous	marker	triceps brachii, endothelial cell, gluteal muscle
MTO1	284	ubiquitous	marker	germinal epithelium of ovary, sperm, endothelial cell
NUBPL	267	ubiquitous	marker	calcaneal tendon, adrenal tissue, skeletal muscle tissue of biceps brachii
SERAC1	214	ubiquitous	marker	epithelial cell of pancreas, endothelial cell, islet of Langerhans
RMND1	273	ubiquitous	marker	primordial germ cell in gonad, ganglionic eminence, calcaneal tendon
MTFMT	245	ubiquitous	marker	left ventricle myocardium, buccal mucosa cell, cardiac muscle of right atrium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FARS2	2,506
MTO1	2,309
MTFMT	2,143
NUBPL	1,696
RMND1	1,354
SERAC1	885

Intra-cohort edges

A	B	Sources
MTFMT	MTO1	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 5 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FARS2	O95363	9

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MTFMT	Q96DP5	86.08
MTO1	Q9Y2Z2	85.95
NUBPL	Q8TB37	85.40
SERAC1	Q96JX3	78.66
RMND1	Q9NWS8	70.28

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 6 evidence-associated genes (4 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
tRNA modification in the mitochondrion	1	259.6×	0.031	MTO1
Mitochondrial tRNA aminoacylation	1	129.8×	0.031	FARS2
tRNA processing	1	89.2×	0.031	MTO1
tRNA Aminoacylation	1	71.4×	0.031	FARS2
Complex I biogenesis	1	41.4×	0.043	NUBPL
Mitochondrial translation initiation	1	31.7×	0.047	MTFMT
Translation	1	15.5×	0.081	FARS2
Metabolism of RNA	1	10.4×	0.104	MTO1
Metabolism of proteins	1	3.1×	0.286	FARS2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
conversion of methionyl-tRNA to N-formyl-methionyl-tRNA	1	2808.7×	0.005	MTFMT
mitochondrial tRNA wobble uridine modification	1	1404.3×	0.005	MTO1
phenylalanyl-tRNA aminoacylation	1	702.2×	0.007	FARS2
phosphatidylglycerol acyl-chain remodeling	1	312.1×	0.012	SERAC1
intracellular cholesterol transport	1	216.1×	0.013	SERAC1
positive regulation of mitochondrial translation	1	187.2×	0.013	RMND1
tRNA aminoacylation for protein translation	1	140.4×	0.013	FARS2
tRNA processing	1	140.4×	0.013	FARS2
phospholipid biosynthetic process	1	112.3×	0.014	SERAC1
iron-sulfur cluster assembly	1	100.3×	0.014	NUBPL
tRNA methylation	1	96.8×	0.014	MTO1
mitochondrial respiratory chain complex I assembly	1	68.5×	0.018	NUBPL
mitochondrion organization	1	25.3×	0.045	NUBPL
extracellular matrix organization	1	20.4×	0.052	SERAC1
translation	1	17.1×	0.057	RMND1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 1 of 6 evidence-associated genes (17%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FARS2	0	0
MTO1	0	0
NUBPL	0	0
SERAC1	0	0
RMND1	0	0
MTFMT	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
FARS2	3	Binding:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FARS2	6.1.1.20	phenylalanine-tRNA ligase
MTFMT	2.1.2.9	methionyl-tRNA formyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	FARS2
D	Druggable family + AlphaFold only, no drug	1	MTFMT
E	Difficult family or no structure, no drug	4	MTO1, NUBPL, SERAC1, RMND1

Undrugged target profiles

6 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
FARS2	3	—
MTO1	0	—
NUBPL	0	—
SERAC1	0	—
RMND1	0	—
MTFMT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.