| Aspect | Key findings | Best supporting sources (with year) | URL/DOI |
|---|---|---|---|
| Enzyme activity | Human AGK is the verified mitochondrial acylglycerol kinase (also called MuLK/MULK), a multi-substrate lipid kinase; a conserved GDG-motif mutation (G126E) abolishes lipid phosphorylation, supporting direct catalytic activity (pqac-00000003, pqac-00000001) | Vukotic et al., 2017; Mayr et al., 2012 | https://doi.org/10.1016/j.molcel.2017.06.013 ; https://doi.org/10.1016/j.ajhg.2011.12.005 |
| Substrates/products | AGK phosphorylates monoacylglycerol (MAG) to lysophosphatidic acid (LPA) and diacylglycerol (DAG) to phosphatidic acid (PA); 2023 review places AGK as an intramitochondrial PA-generating route in the inner mitochondrial membrane (pqac-00000004, pqac-00000007, pqac-00000021) | Jackson et al., 2021; Siriwardena et al., 2013; Joshi et al., 2023 | https://doi.org/10.1091/mbc.e20-06-0390 ; https://doi.org/10.1016/j.ymgme.2012.11.282 ; https://doi.org/10.1242/jcs.260857 |
| Localization/topology | AGK is exclusively mitochondrial by fractionation; protease-protection assays indicate an intermembrane-space (IMS) localization associated with the inner membrane without predicted transmembrane spans (pqac-00000003, pqac-00000025) | Vukotic et al., 2017 | https://doi.org/10.1016/j.molcel.2017.06.013 |
| TIM22 role | AGK is a bona fide subunit of the human TIM22 translocase; AGK, TIMM22, and TIMM29 co-migrate in a ~400 kDa complex, and AGK loss disrupts assembly so TIMM22 shifts to ~90 kDa and TIMM29 mainly to ~60 kDa species (pqac-00000003, pqac-00000005, pqac-00000025) | Vukotic et al., 2017 | https://doi.org/10.1016/j.molcel.2017.06.013 |
| TIM22 substrate import | AGK supports import/accumulation of carrier proteins including ANT1, ANT3, and SLC25A24; ANT1 import is significantly impaired but not abolished in AGK-null mitochondria; rescue by kinase-dead G126E shows the import role is kinase-independent (pqac-00000002, pqac-00000005) | Vukotic et al., 2017 | https://doi.org/10.1016/j.molcel.2017.06.013 |
| Expanded pathway role | AGK/TIM22 is also required for import of sideroflexins (SFXNs), identifying a novel TIM22 substrate class and linking AGK deficiency to impaired mitochondrial one-carbon metabolism and serine dependence (pqac-00000004, pqac-00000024) | Jackson et al., 2021 | https://doi.org/10.1091/mbc.e20-06-0390 |
| Lipid metabolism pathway context | PA generated by AGK in the IMM is positioned upstream of other mitochondrial phospholipids, including cardiolipin biosynthesis; expert reviews interpret AGK as linking mitochondrial phospholipid homeostasis with OXPHOS function (pqac-00000009, pqac-00000021) | Vukotic et al., 2017; Joshi et al., 2023 | https://doi.org/10.1016/j.molcel.2017.06.013 ; https://doi.org/10.1242/jcs.260857 |
| Structure/cristae and apoptosis | AGK’s kinase activity is dispensable for TIM22 assembly but required for mitochondrial cristae maintenance and apoptotic resistance; catalytically inactive AGK behaves like knockout for cristae/apoptosis phenotypes (pqac-00000002, pqac-00000023) | Vukotic et al., 2017 | https://doi.org/10.1016/j.molcel.2017.06.013 |
| Disease association | Biallelic loss-of-function AGK variants cause Sengers syndrome, classically featuring congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy/exercise intolerance, and lactic acidosis; AGK is the established disease gene in Open Targets and primary genetics studies (pqac-00000014, pqac-00000012, pqac-00000000) | Mayr et al., 2012; Open Targets | https://doi.org/10.1016/j.ajhg.2011.12.005 ; https://platform.opentargets.org |
| Variant spectrum / cohort data | In one foundational cohort, AGK sequencing in 13 individuals with congenital cataracts and cardiomyopathy identified 12 predicted loss-of-function alleles in 10 affected individuals; historical summary in the same report noted ~40 individuals described overall by 2012 (pqac-00000012, pqac-00000014) | Mayr et al., 2012 | https://doi.org/10.1016/j.ajhg.2011.12.005 |
| Quantitative mitochondrial protein loss | In patient muscle, AGK protein can be nearly absent/negligible, with mitochondrial immunogold labeling reduced from 37.9±4.6 particles/μm² in control to 14.5±4.9 and 18.9±6.9 particles/μm² in two AGK-deficient patients (pqac-00000007, pqac-00000013) | Siriwardena et al., 2013 | https://doi.org/10.1016/j.ymgme.2012.11.282 |
| Quantitative bioenergetic defects | Patient fibroblasts showed decreased complex I activity to 43% and 54% of control in two cases, with high lactate/pyruvate ratios; another index case had plasma lactate 7.3 mmol/L (normal 0.5–2.2 mmol/L) (pqac-00000013, pqac-00000014) | Siriwardena et al., 2013; Mayr et al., 2012 | https://doi.org/10.1016/j.ymgme.2012.11.282 ; https://doi.org/10.1016/j.ajhg.2011.12.005 |
| Severe neonatal phenotype | A 2021 functionally characterized splice variant (c.518+1G>A) caused fatal neonatal Sengers syndrome with congenital cataracts, dilated cardiomyopathy, hyperlactacidemia, death at 20 h, plus reduced OCR and decreased OXPHOS complexes I and V in fibroblasts (pqac-00000008, pqac-00000010) | Barbosa-Gouveia et al., 2021 | https://doi.org/10.3390/ijms222413484 |
| Clinical heterogeneity | AGK disease ranges from lethal neonatal/infantile disease to milder forms, including reports of isolated congenital cataract without major cardiomyopathy in some families, indicating variable expressivity despite shared mitochondrial mechanism (pqac-00000014, pqac-00000019) | Mayr et al., 2012; Siriwardena et al., 2013 | https://doi.org/10.1016/j.ajhg.2011.12.005 ; https://doi.org/10.1016/j.ymgme.2012.11.282 |


*Table: This table summarizes the experimentally supported functions, localization, pathway roles, and disease relevance of human AGK (UniProt Q53H12). It emphasizes quantitative findings and the strongest supporting sources for functional annotation.*