Biology subjects

Distelmaier, F.

Publications and source records attributed to Distelmaier, F..

5 recordsLinked to original sources

bioRxiv2026

L-2-hydroxyglutarate recycling is linked to coenzyme Q biosynthesis

The mitochondrial COQ metabolon catalyzes the late stages of the biosynthesis of coenzyme Q, an essential and ubiquitous cofactor. Here, by integrating coevolution, coexpression, colocalization and domain-fusion analyses, we identify L-2-hydroxyglutarate dehydrogenase (L2HGDH) as an integral component of this assembly. By acting in physical proximity to the COQ metabolon, L2HGDH sustains coenzyme Q production by maintaining the biosynthetic intermediates in their catalytically-active reduced state. Consistently, analysis of fibroblasts and urine samples from patients with primary coenzyme Q deficiency displayed marked accumulation of L-2-hydroxyglutarate. Cryo-electron microscopy reveals that L2HGDH forms a stable complex with COQ3 and COQ6, defining a heterotrimeric assembly that organizes catalytic sites on a shared membrane-facing surface thereby enabling localized quinone reduction. Together, these findings identify L2HGDH as a previously unrecognized component of the COQ metabolon, establish a direct link between central carbon metabolism and coenzyme Q biosynthesis, and expand the functional roles of metabolons in coordinating metabolic flux across distinct pathways.

biochemistry↗

bioRxiv2026

MIC13-linked cristae disruption causes metabolic failure and early fibrotic remodelling in mitochondrial liver disease

Mitochondrial diseases are highly complex and heterogeneous, and nearly 20% of cases involve severe liver pathology. Here, we report an affected individual carrying a pathogenic MIC13 variant (c.260-2A>G) associated with early-onset mitochondrial hepato-encephalopathy. Such mitochondrial hepatopathies are rare, multisystemic disorders with major liver involvement, difficult to diagnose, lack effective treatment, and are poorly understood, in part due to the absence of faithful disease-relevant cellular models. To investigate hepatocyte-specific consequences of the MIC13 variant, we generated iPSCs carrying this disease-causing variant and differentiated them into induced hepatocytes (iHeps). MIC13, a key component of the MICOS complex required for cristae formation, was disrupted in these cells, and the resultant iHeps exhibited the same cristae defects observed in clinical samples. Integrated multi-omics and biochemical analyses revealed extensive metabolic rewiring, including disrupted amino acid turnover and accumulation of tricarboxylic acid (TCA) and urea cycle intermediates. Additionally, profound alterations in methionine cycle and transsulfuration pathways, along with enhanced bile acid synthesis, collectively affect methylation potential, redox homeostasis, and detoxification. Lipid metabolism was also impaired, with incomplete {beta}-oxidation, increased ketogenesis, and diminished lipid storage. At the cellular level, extensive extracellular matrix (ECM) remodelling, increased intracellular collagen accumulation and enhanced cell migration indicated an early fibrotic phenotype. Overall, this clinically relevant model uncovers mechanistically how cristae defects drive metabolic imbalance and hepatocyte dysfunction, ultimately leading to early fibrotic changes in mitochondrial liver disease. These findings provide a strong mechanistic foundation for understanding mitochondrial liver disease and developing targeted therapeutic strategies.

biochemistry↗

bioRxiv2024

Deep learning-driven neuromorphogenesis screenings identify repurposable drugs for mitochondrial disease

Mitochondrial disease encompasses untreatable conditions affecting tissues with high energy demands. A severe manifestation of mitochondrial disease is Leigh syndrome (Leigh), which causes defects in basal ganglia and midbrain regions, psychomotor regression, lactic acidosis, and early death. We previously generated isogenic pairs of Leigh cerebral organoids and uncovered defects in neuromorphogenesis. Here, we leveraged on this disease feature to devise drug discovery pipelines. We developed a deep learning algorithm tailored for cell type-specific drug repurposing to identify drugs capable of promoting neuronal commitment. In parallel, we performed a survival drug screen in yeast and validated the repurposable hits on branching capacity in Leigh neurons. The two approaches independently highlighted azole compounds, Talarozole and Sertaconazole, both of which lowered lactate release and improved neurogenesis and neurite organization in Leigh midbrain organoids. Hence, targeting neuromorphogenesis has led to identify potential new drugs for mitochondrial disease and could prove an effective strategy for further drug discovery.

neuroscience↗

bioRxiv2024

Epg5 links proteotoxic stress due to defective autophagic clearance and epileptogenesis in Drosophila and Vici Syndrome patients

Epilepsy is a common neurological condition that arises from dysfunctional neuronal circuit control due to either acquired or innate disorders. Autophagy is an essential neuronal housekeeping mechanism, which causes severe proteotoxic stress when impaired. Autophagy impairment has been associated to epileptogenesis through a variety of molecular mechanisms. Vici Syndrome (VS) is the paradigmatic congenital autophagy disorder in humans due to recessive variants in the ectopic P-granules autophagy tethering factor 5 (EPG5) gene that is crucial for autophagosome-lysosome fusion and ultimately for effective autophagic clearance. VS is characterized by a wide range of neurodevelopmental, neurodegenerative, and neurological features, including epilepsy. Here, we used Drosophila melanogaster to study the importance of epg5 in development, ageing, and seizures. Our data indicate that proteotoxic stress due to impaired autophagic clearance and seizure-like behaviors correlate and are commonly regulated, suggesting that seizures occur as a direct consequence of proteotoxic stress and age-dependent neurodegenerative progression in epg5 Drosophila mutants, in the absence of evident neurodevelopmental abnormalities. We provide complementary evidence from EPG5-mutated patients demonstrating an epilepsy phenotype consistent with Drosophila predictions and propose autophagy stimulating diets as a feasible approach to control EPG5-related pharmacoresistant seizures.

neuroscience↗

bioRxiv2020

Lutein restores synaptic functionality in a C. elegans model for mitochondrial complex I deficiency

Complex I deficiency represents the most frequent pathogenetic cause of human mitochondriopathies. Therapeutic options for these neurodevelopmental life-threating disorders do not exist, partly due to the scarcity of appropriate model systems to study them. Caenorhabditis elegans is a genetically tractable model organism widely used to investigate neuronal pathologies. Here, we generated new C. elegans models for mitochondriopathies and showed that depletion of Complex I subunits recapitulates biochemical, cellular and neurodevelopmental aspects of the human diseases. Two models, nuo-5/NDUFS1- and lpd-5/NDUFS4-depleted animals, were exploited for a suppressor screening that identified lutein for its ability to rescue animals neurodevelopmental deficits. We uncovered overexpression of synaptic neuroligins as an evolutionarily conserved consequence of mitochondrial dysfunction, which we found to mediate an early cholinergic defect in C. elegans. We showed lutein exerts its beneficial effects by restoring neuroligin expression independently from its antioxidant activity, thus pointing to a possible novel pathogenetic target for the human disease.

neuroscience↗