Mitochondrial encephalomyopathy

Summary

Mitochondrial encephalomyopathy (MONDO:0004675) is a disease with 10 cohort genes and 6 clinical trials. Top therapeutic interventions include sonlicromanol and doxecitine.

At a glance

• Cohort genes: 10
• ClinVar variants: 9
• Clinical trials: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	mitochondrial encephalomyopathy
Mondo ID	MONDO:0004675
MeSH	D017237
DOID	DOID:890
SNOMED CT	447292006
UMLS	C0162666
MedGen	57960
GARD	0024084
Is cancer (heuristic)	no

Data availability: 9 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › congenital myopathy › congenital structural myopathy › inborn mitochondrial myopathy › mitochondrial encephalomyopathy

Related subtypes (23): myopathy, lactic acidosis, and sideroblastic anemia, progressive external ophthalmoplegia, mitochondrial myopathy with a defect in mitochondrial-protein transport, Barth syndrome, mitochondrial myopathy with diabetes, mitochondrial myopathy with reversible cytochrome C oxidase deficiency, lethal infantile mitochondrial myopathy, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, mitochondrial trifunctional protein deficiency, adenosine monophosphate deaminase deficiency, congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome, autosomal dominant mitochondrial myopathy with exercise intolerance, fatal infantile encephalocardiomyopathy, mitochondrial myopathy-lactic acidosis-deafness syndrome, mitochondrial neurogastrointestinal encephalomyopathy, adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy, maternally-inherited progressive external ophthalmoplegia, mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy, mitochondrial complex II deficiency, nuclear type, mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome, X-linked recessive mitochondrial myopathy, mitochondrial complex I deficiency, nuclear type 1, COX deficiency, benign infantile mitochondrial myopathy

Subtypes (2): MELAS syndrome, MERRF syndrome

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

9 retrieved; paginated sample, class counts are floors:

4 likely pathogenic, 2 uncertain significance, 2 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
66093	NM_001278716.2(FBXL4):c.1444C>T (p.Arg482Trp)	FBXL4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39824	NM_006567.5(FARS2):c.431A>G (p.Tyr144Cys)	LOC126859565	Pathogenic	criteria provided, multiple submitters, no conflicts
39831	NM_001277062.2(MFF):c.112C>T (p.Gln38Ter)	MFF	Pathogenic/Likely pathogenic	no assertion criteria provided
9680	NC_012920.1(MT-CYB):m.15242G>A	MT-CYB	Likely pathogenic	reviewed by expert panel
9594	NC_012920.1(MT-TL1):m.3252A>G	MT-TL1	Likely pathogenic	reviewed by expert panel
9586	NC_012920.1(MT-TL2):m.12315G>A	MT-TL2	Likely pathogenic	reviewed by expert panel
30007	NC_012920.1(MT-TW):m.5556G>A	MT-TW	Likely pathogenic	reviewed by expert panel
30000	NC_012920.1(MT-TR):m.10450A>G	MT-TR	Uncertain significance	reviewed by expert panel
9623	NC_012920.1(MT-TR):m.10438A>G	MT-TR	Uncertain significance	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 18 · 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
LONP1	Limited	Autosomal dominant	mitochondrial encephalomyopathy	10
MRPS25	Limited	Autosomal recessive	mitochondrial encephalomyopathy	3
SLIRP	Limited	Autosomal recessive	inborn mitochondrial metabolism disorder	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
LONP1	Orphanet:1458	CODAS syndrome
LONP1	Orphanet:2140	Congenital diaphragmatic hernia
LONP1	Orphanet:79243	Pyruvate dehydrogenase E1-alpha deficiency
FBXL4	Orphanet:369897	Mitochondrial DNA depletion syndrome, encephalomyopathic form with variable craniofacial anomalies
MFF	Orphanet:485421	MFF-related encephalopathy due to mitochondrial and peroxisomal fission defect
MT-CYB	Orphanet:104	Leber hereditary optic neuropathy
MT-CYB	Orphanet:137675	Histiocytoid cardiomyopathy
MT-CYB	Orphanet:1460	Isolated complex III deficiency
MT-TL1	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-TL1	Orphanet:324525	Hypertrophic cardiomyopathy with kidney anomalies due to mitochondrial DNA mutation
MT-TL1	Orphanet:480	Kearns-Sayre syndrome
MT-TL1	Orphanet:550	MELAS
MT-TL1	Orphanet:551	MERRF
MT-TL1	Orphanet:663	Mitochondrial DNA-related progressive external ophthalmoplegia
MT-TL2	Orphanet:2131	Alternating hemiplegia of childhood
MT-TL2	Orphanet:663	Mitochondrial DNA-related progressive external ophthalmoplegia
MT-TW	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-TW	Orphanet:550	MELAS

Cohort genes → proteins

10 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MRPS25	HGNC:14511	ENSG00000131368	P82663	Small ribosomal subunit protein mS25	gencc
SLIRP	HGNC:20495	ENSG00000119705	Q9GZT3	SRA stem-loop-interacting RNA-binding protein, mitochondrial	gencc
LONP1	HGNC:9479	ENSG00000196365	P36776	Lon protease homolog, mitochondrial	gencc
FBXL4	HGNC:13601	ENSG00000112234	Q9UKA2	F-box/LRR-repeat protein 4	clinvar
MFF	HGNC:24858	ENSG00000168958	Q9GZY8	Mitochondrial fission factor	clinvar
MT-CYB	HGNC:7427	ENSG00000198727	P00156	Cytochrome b	clinvar
MT-TL1	HGNC:7490	ENSG00000209082		mitochondrially encoded tRNA-Leu (UUA/G) 1	clinvar
MT-TL2	HGNC:7491	ENSG00000210191		mitochondrially encoded tRNA-Leu (CUN) 2	clinvar
MT-TR	HGNC:7496	ENSG00000210174		mitochondrially encoded tRNA-Arg (CGN)	clinvar
MT-TW	HGNC:7501	ENSG00000210117		mitochondrially encoded tRNA-Trp (UGA/G)	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLIRP	SRA stem-loop-interacting RNA-binding protein, mitochondrial	RNA-binding protein that acts as a nuclear receptor corepressor.
LONP1	Lon protease homolog, mitochondrial	ATP-dependent serine protease that mediates the selective degradation of misfolded, unassembled or oxidatively damaged polypeptides as well as certain short-lived regulatory proteins in the mitochondrial matrix.
FBXL4	F-box/LRR-repeat protein 4	Substrate-recognition component of the mitochondria-localized SCF-FBXL4 ubiquitin E3 ligase complex that plays a role in the restriction of mitophagy by controlling the degradation of BNIP3 and NIX mitophagy receptors.
MFF	Mitochondrial fission factor	Plays a role in mitochondrial and peroxisomal fission.
MT-CYB	Cytochrome b	Component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex) that is part of the mitochondrial respiratory chain.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 9 · Druggable fraction: 0.1

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
Other/Unknown	9	1.6×	0.052
Protease	1	3.7×	0.242

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MRPS25	Other/Unknown	no		Ribosomal_mL43/mS25/NADH_DH, Thioredoxin-like_sf, Ribosomal_mS25/mL61
SLIRP	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, SLIRP_RRM
LONP1	Protease	yes	3.4.21.53	Lon_prtase_N, AAA+_ATPase, ATPase_AAA_core
FBXL4	Other/Unknown	no		F-box_dom, Leu-rich_rpt_Cys-con_subtyp, LRR_dom_sf
MFF	Other/Unknown	no		Mff/Tango-11, Mff-like_dom
MT-CYB	Other/Unknown	no		Cyt_b/b6_N, Cyt_b/b6_C, Di-haem_cyt_TM
MT-TL1	Other/Unknown	no
MT-TL2	Other/Unknown	no
MT-TR	Other/Unknown	no
MT-TW	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

7 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)	10
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	4
caudate nucleus	2
sural nerve	2
pancreatic ductal cell	1
right lobe of thyroid gland	1
C1 segment of cervical spinal cord	1
hindlimb stylopod muscle	1
mucosa of transverse colon	1
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1
adrenal tissue	1
calcaneal tendon	1
corpus epididymis	1
left testis	1
right testis	1
sperm	1
pituitary gland	1
zone of skin	1
frontal cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MRPS25	260	ubiquitous	marker	apex of heart, pancreatic ductal cell, right lobe of thyroid gland
SLIRP	287	ubiquitous	marker	mucosa of transverse colon, hindlimb stylopod muscle, C1 segment of cervical spinal cord
LONP1	275	ubiquitous	marker	right adrenal gland, right adrenal gland cortex, left adrenal gland
FBXL4	265	ubiquitous	marker	adrenal tissue, corpus epididymis, calcaneal tendon
MFF	290	ubiquitous	marker	sperm, left testis, right testis
MT-CYB	134	ubiquitous	marker	apex of heart, pituitary gland, zone of skin
MT-TL1	118	ubiquitous	marker	frontal cortex, right frontal lobe, caudate nucleus
MT-TL2	118	broad	yes	apex of heart, putamen, caudate nucleus
MT-TR	116	tissue_specific	yes	sural nerve, skeletal muscle tissue, apex of heart
MT-TW	114	ubiquitous	yes	sural nerve, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LONP1	4,030
SLIRP	3,455
MT-CYB	3,317
MRPS25	2,539
MFF	2,460
FBXL4	1,620
MT-TL1	0
MT-TL2	0
MT-TR	0
MT-TW	0

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 4

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MRPS25	P82663	77
LONP1	P36776	29
MT-CYB	P00156	5
SLIRP	Q9GZT3	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FBXL4	Q9UKA2	86.50
MFF	Q9GZY8	64.74

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 10 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitochondrial translation termination	2	43.9×	0.015	MRPS25, MT-CYB
Mitochondrial RNA degradation	1	326.3×	0.028	SLIRP
Mitochondrial mRNA modification	1	207.6×	0.029	SLIRP
Mitochondrial unfolded protein response (UPRmt)	1	120.2×	0.037	LONP1
Complex III assembly	1	87.8×	0.041	MT-CYB
Mitochondrial translation	1	27.5×	0.077	MRPS25
Mitochondrial translation initiation	1	25.4×	0.077	MRPS25
Mitochondrial translation elongation	1	25.4×	0.077	MRPS25
Mitochondrial ribosome-associated quality control	1	24.6×	0.077	MRPS25
Mitochondrial protein degradation	1	22.8×	0.077	LONP1
Respiratory electron transport	1	19.0×	0.083	MT-CYB
Metabolism of proteins	2	5.0×	0.083	MRPS25, LONP1
Translation	1	12.4×	0.108	MRPS25
Neddylation	1	9.5×	0.130	FBXL4
Metabolism of RNA	1	8.3×	0.136	SLIRP
Antigen processing: Ubiquitination & Proteasome degradation	1	7.4×	0.136	FBXL4
Cellular responses to stress	1	7.4×	0.136	LONP1
Cellular responses to stimuli	1	6.3×	0.149	LONP1

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
mitochondrion organization	3	75.9×	2e-04	SLIRP, MFF, LONP1
response to D-galactosamine	1	2808.7×	0.006	MT-CYB
response to cobalamin	1	1404.3×	0.006	MT-CYB
oxidation-dependent protein catabolic process	1	1404.3×	0.006	LONP1
negative regulation of mitochondrial mRNA catabolic process	1	1404.3×	0.006	SLIRP
response to aluminum ion	1	936.2×	0.007	LONP1
electron transport coupled proton transport	1	702.2×	0.007	MT-CYB
mitochondrial mRNA polyadenylation	1	702.2×	0.007	SLIRP
response to hypoxia	2	31.9×	0.007	MT-CYB, LONP1
response to mercury ion	1	401.2×	0.010	MT-CYB
response to glucagon	1	280.9×	0.010	MT-CYB
peroxisome fission	1	255.3×	0.010	MFF
mitochondrial protein catabolic process	1	255.3×	0.010	LONP1
response to copper ion	1	255.3×	0.010	MT-CYB
negative regulation of mitophagy	1	255.3×	0.010	FBXL4
mitochondrial electron transport, ubiquinol to cytochrome c	1	216.1×	0.012	MT-CYB
response to hyperoxia	1	187.2×	0.013	MT-CYB
mitochondrial fission	1	175.5×	0.013	MFF
protein quality control for misfolded or incompletely synthesized proteins	1	127.7×	0.015	LONP1
positive regulation of mitochondrial fission	1	127.7×	0.015	MFF
autophagy of mitochondrion	1	122.1×	0.015	FBXL4
response to cadmium ion	1	122.1×	0.015	MT-CYB
chaperone-mediated protein complex assembly	1	117.0×	0.015	LONP1
animal organ regeneration	1	100.3×	0.016	MT-CYB
obsolete protein targeting to mitochondrion	1	96.8×	0.016	MFF
obsolete proteolysis involved in protein catabolic process	1	87.8×	0.017	LONP1
response to hormone	1	72.0×	0.020	LONP1
cellular respiration	1	72.0×	0.020	MT-CYB
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	1	62.4×	0.021	FBXL4
negative regulation of insulin receptor signaling pathway	1	62.4×	0.021	LONP1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 9

Druggability breadth: 2 of 10 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
LONP1	BORTEZOMIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LONP1	1	4
MRPS25	0	0
SLIRP	0	0
FBXL4	0	0
MFF	0	0
MT-CYB	0	0
MT-TL1	0	0
MT-TL2	0	0
MT-TR	0	0
MT-TW	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BORTEZOMIB	4	LONP1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
LONP1	2	Binding:2
SLIRP	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
LONP1	3.4.21.53	Endopeptidase La

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
BORTEZOMIB	4	LONP1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	LONP1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	9	MRPS25, SLIRP, FBXL4, MFF, MT-CYB, MT-TL1, MT-TL2, MT-TR, MT-TW

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MRPS25	0	—
SLIRP	1	—
FBXL4	0	—
MFF	0	—
MT-CYB	0	—
MT-TL1	0	—
MT-TL2	0	—
MT-TR	0	—
MT-TW	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	3
Not specified	2
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT06051448	PHASE1/PHASE2	COMPLETED	Promoting Resilience in Stress Management (PRISM) and Clinical-focused Narrative (CFN) Pilot in Adults With Primary Mitochondrial Disease (PMD).
NCT05848271	Not specified	RECRUITING	Natural History Study of Patients with HPDL Mutations
NCT06213090	Not specified	RECRUITING	Patterns of Neurodevelopmental Disorders

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SONLICROMANOL	3	2
DOXECITINE	2	1