Table 1.

Classification of nuclear gene related mitochondrial disease based on the gene function [1, 5, 16, 20, 71, 76, 94]

	Gene	Inheritance	Onset	Common clinical manifestation/syndrome
OXPHOS system
Complex I
Structural subunit	NDUFA2, NDUFA9, NDUFA10, NDUFA11, NDUFA12, NDUFA13, NDUFB3, NDUFB9, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS6, NDUFS7, NDUFS8	AR	Infancy	Leigh syndrome, encephalopathy, cardiomyopathy, epilepsy, lactic acidosis
	NDUFA1, NDUFB11	X-linked		Leigh syndrome, microphthalmia with linear skin defects
Assembly factor	ACAD9, NDUFAF1, NDUFAF2, NDUFAF4, NDUFAF5, NDUFAF6, FOXRED1	AR		Leigh syndrome, encephalopathy, cardiomyopathy
Complex II
Structural subunit	SDHA-D	AR	Infancy, childhood	Leigh syndrome, dilated cardiomyopathy
		AD	Childhood, adulthood	Hereditary paraganglioma, pheochromocytoma
Assembly factor	SDHAF1	AR	Infancy	Spastic quadriplegia, leukodystrophy
	SDHAF2	AD	Adulthood	Hereditary paraganglioma, pheochromocytoma
Complex III
Structural subunit	UQCRB	AR	Childhood	Hypoglycaemia, lactic acidosis
	UQCRQ	AR	Childhood	Extrapyramidal signs, ataxia, psychomotor retardation
Assembly factor	BCS1L	AR	Infancy	Growth retardation, aminoaciduria, cholestasis, iron overload, and early death (GRACILE)
	TTC19	AR	Childhood, adulthood	Encephalomyopathy, ataxia
Complex IV
Structural subunit	COX6B1, NDUFA4	AR	Infancy, childhood	Encephalomyopathy, Leigh-like syndrome
	COX4I2	AR	Infancy, childhood	Exocrine pancreatic insufficiency, dyserythropoetic anaemia (similar to Pearson syndrome), calvarial hyperostosis
Assembly factor	SURF1, SCO1-2, COX10, COX15, LRPPRC, COA5, PET100	AR	Infancy	Leigh syndrome, French-Canadian Leigh syndrome, hypertrophic cardiomyopathy, encephalomyopathy
Complex V
Structural subunit	ATP5E	AR	Infancy	Encephalopathy, dysmorphic features, hypertrophic cardiomyopathy, lactic acidosis
Assembly factor	ATPAF2, TMEM70	AR
Co-enzyme Q10 biosynthesis
Co-enzyme Q10 deficiency	COQ2, COQ4, COQ6, PDSS2	AR	Infancy, childhood	Encephalomyopathy, nephrotic syndrome, sensori-neural deafness
	ETFDH	AR	Infancy, childhood, adulthood	Glutaric acidaemia IIC (multiple acyl-CoA dehydrogenase deficiency, MADD), Myopathy
	ADCK3	AR	Childhood	Cerebellar ataxia
Mitochondrial DNA replication
MtDNA depletion or multiple deletions	POLG	AD	Adulthood	Chronic progressive external ophthalmoplegia (CPEO)
		AR	Infancy, childhood, adulthood	CPEO, Alpers disease, ataxia-neuropathy syndrome, Leigh syndrome, epilepsy (occipital), Parkinsonism
	PEO1 (c10orf2)	AD	Adulthood	CPEO
		AR	Infancy	Inherited Infancy onset of spinocerebellar ataxia (IOSCA), hepatocerebral syndrome
MtDNA multiple deletions	POLG2	AD	Adulthood	CPEO
Nucleotide synthesis and transport (maintenance)
MtDNA depletion or multiple deletions	TYMP	AR	Childhood, adulthood	Mitochondrial neuro-gastrointestinal encephalomyopathy (MNGIE)
	RRM2B	AD	Adulthood	CPEO
		AR	Infancy	Encephalomyopathy, gut dysmotility, Kearns-Sayre syndrome (KSS), proximal renal tubulopathy
	SLC25A4 (ANT1)	AD	Adulthood	CPEO
		AR	Childhood	Hypertrophic cardiomyopathy, lactic acidosis
	TK2	AR	Infancy, childhood, adulthood	Myopathy and respiratory muscle weakness
	MPV17	AR	Infancy, childhood, adulthood	Hepatocerebral syndrome, neuropathy and leukoencephalopathy
MtDNA depletion	DGUOK	AR	Infancy	Hepatocerebral syndrome
	SUCLA2, SUCLG1	AR	Infancy	Encephalomyopathy, raised methylmalonic acid, hyperkinesia
MtDNA multiple deletions	DNA2	AD	Adulthood	CPEO
No change in mtDNA content/unknown	SLC25A3	AR	Infancy	Hypertrophic cardiomyopathy, hypotonia
	GFER	AR	Childhood, adulthood	Congenital cataract, myopathy, cardiomyopathy
Mitochondrial translation
Multiple respiratory chain deficiency
Ribosomal protein	MRPS16	AR	Infancy	Dysmorphism, lactic acidosis, agenesis of corpus callosum
	MRPS22	AR	Infancy	Cardiomyopathy, tubulopathy, hypotonia
Elongation factor	GFM1, TUFM	AR	Infancy	Leigh syndrome
	TSFM	AR	Infancy, childhood	Encephalopathy, hypertrophic cardiomyopathy
tRNA modification	PUS1	AR	Infancy, childhood	Myopathy, lactic acidosis and sideroblastic anaemia (MLASA)
	MTFMT	AR	Infancy, childhood	Encephalomyopathy
	TRIT1	AR	Childhood	Encephalopathy, myoclonic epilepsy
tRNA synthetases	AARS2	AR	Infancy	Hypertrophic cardiomyopathy, myopathy
	CARS2	AR	Childhood	Epileptic encephalopathy, myoclonus
	DARS2	AR	Childhood, adulthood	Leukoencephalopathy in brainstem and spinal cord involvement and lactate elevation (LBSL)
	EARS2	AR	Infancy, childhood	Leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL)
	GARS	AD	Childhood, adulthood	Charcot-Marie-Tooth 2D, Hereditary motor neuropathy 5A
	MARS2	AR	Childhood, adulthood	Autosomal recessive spastic ataxia and leukoencephalopathy (ARSAL) in French Canadians
	RARS2	AR	Infancy	Pontocerebellar hypoplasia type 6
	SARS2	AR	Infancy	Tubulopathy (hyperuricemia, metabolic alkalosis), pulmonary hypertension, and progressive renal failure (HUPRA)
	YARS2	AR	Childhood, adulthood	MLASA
Mitochondrial dynamic network (mitochondrial membrane biogenesis and maintenance)
Fusion	MFN2	AD	Childhood, adulthood	Charcot-Marie-Tooth 2A (CMT2A) (multiple deletions)
	OPA1	AD	Childhood	Optic atrophy (multiple deletions)
	OPA3	AD	Adulthood	Optic atrophy
		AR	Infancy, childhood	Type III 3-methylglutaconic aciduria, Costeff syndrome
	PINK1	AR	Childhood, adulthood	Juvenile Parkinson Disease
Fission	DNM1L (DRP1)	AR	Infancy	Microcephaly, lactic acidosis, optic atrophy

AR autosomal recessive, AD autosomal dominant