Leigh syndrome (LS) is an incurable and rare mitochondrial disorder affecting infants and children. LS is clinically and genetically heterogeneous, resulting in a diverse phenotypic spectrum that includes neurological symptoms, with severe brainstem dysfunction (1). Known mutations affecting the mitochondrial electron transport chain have been described and contribute to the pathogenesis of LS (2).

Many genes present in the network have a known association with LS as represented in the QKG. Indeed, the LS network includes a set of genes that encode subunits of the mitochondrial respiratory chain either from mitochondrial DNA origin: MT-ATP6 (Complex V), MT-CO1 (Complex IV), MT-ND5 (Complex I), MT-CYB (Complex III); or from nuclear DNA origin: NDUFA10 (Complex I), MTFMT, COX15 SURF1 LRPPRC (Complex III). Most of these genes have known pathogenic mutations that disrupt and reduce the normal process of oxidative phosphorylation. Neuromuscular and ocular abnormalities are among the consequences of decreased OXPHOS capacity, but cardiomyopathies and gastrointestinal/renal dysfunctions are also observed.

Other known genes such as LONP1 (a mitochondrial matrix protease with a role in selective degradation of oxidatively damaged protein, ClinGen) or RANBP2 (nuclear pore complex protein involved in the RAN-GTPase cycle) or NUBPL (required for the assembly of the NADH dehydrogenase (Complex I) have been associated to LS as well (ClinVar).

The network contains 43 genes predicted to be associated with LS: (ABCC8, ACLY, ADCY3, BACH1, CA9, CALU, CLPP, COX6A2, DAP3, DDX5, DNMT1, H2AX, HBA1/HBA2, Hbb-b1, HK2, IGFR1, IL2RA, INSR, KCNJ11, KDM5A, LDHB, MARCHF6, MCU, MTNR1A, MTNR1B, NR4A3, OMA1, PCK1, PDYN, PPARGC1B, PTCD1, RB1, RC3H2, RICTOR, SERTAD2, SIRT3, SLC27A2, SLC3A2, TFAM, TP53, UBE2I, YARS2, ZBTB7B). None of these currently have known connections with LS directly in our QKG. However, many have direct or indirect molecular connections with some aspect of mitochondrial function. For instance, ATP citrate lyase (ACLY) is involved in the transfer of Acetyl-CoA from mitochondria to cytoplasm for the regulation of lipid and cholesterol metabolism (3). Others are key regulators of mitochondrial biogenesis (PPARGC1B, TFAM, IGFR1) (4). Furthermore, several have been linked to ocular dysfunction, which is one of the LS clinical features. A recent study in Zebrafish demonstrated that the mitochondrial tyrosyl-tRNA synthetase YARS2 is involved in the stability and activity of OXPHOS, and mutated YARS2 is linked to optic neuropathy (5). This network also contains proteins involved in key biological processes such as apoptosis (DAP3 is a mitochondrial ribosomal protein) (QKG). PTCD1 is another ribosomal RNA maturation protein possibly linked to Alzheimer's Disease, highlighting a potential molecular connection between mitochondrial function and neurological disorders (6). Finally, important epigenetic factors such as SIRT3 or DNMT1 are present in the LS network. SIRT3, an NAD+-dependent protein deacetylase, is a mitochondrial sirtuin implicated in many cellular processes (autophagy, regulation of the mitochondrial chain reaction, energy metabolism, and more) and Parkinson Disease (7).


1. Ruhoy, I. S., and Saneto, R. P. (2014) Appl. Clin. Genet. 7, 221-234. PMID: 25419155
2. Bakare AB, et al. (2021) Front Physiol. 12:693734. PMID: 34456746
3. Chen Q, et al. (2021) iScience 24 (11). PMID: 34746707
4. Radovic SM, et al. (2019) Biol Reprod. 100(1), 253-267 PMID: 30084987
5. Jin X, et al. (2021) J Biol Chem. 296:100437 PMID: 33610547
6. Fleck D, et al. (2019) J Neurosci. 39(24):4636-4656. PMID: 30948477
7. He L, et al. (2022) Neurochem Res. doi: 10.1007/s11064-022-03560-w. PMID: 35220492