Biology subjects

Herebian, D.

Publications and source records attributed to Herebian, D..

3 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↗

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↗

bioRxiv2023

The response to ketogenic diet in colorectal cancer is mediated by lasting functional alterations of the gut microbiome

Colorectal cancer (CRC) patients have been shown to possess an altered gut microbiome. Diet is a well-established modulator of the microbiome, and thus, dietary interventions might have a beneficial effect on CRC. An attenuating effect of the ketogenic diet (KD) on CRC cell growth has been previously observed, however the role of the gut microbiome in driving this effect remains unknown. Here, we describe a reduced colonic tumor burden upon KD consumption in a CRC mouse model with a humanized microbiome. Importantly, we demonstrate a causal relationship through microbiome transplantation into germ-free mice, whereby alterations in the gut microbiota were maintained in the absence of continued selective pressure from the KD. Specifically, we identify a shift toward bacterial species that produce stearic acid in ketogenic conditions, whereas consumers were depleted, resulting in elevated levels of free stearate in the gut lumen. This microbial product demonstrated tumor-suppressing properties by inducing apoptosis in cancer cells and decreasing colonic Th17 immune cell populations. Taken together, the beneficial effects of the KD are mediated through alterations in the gut microbiome, including, among others, increased stearic acid production, which in turn significantly reduces intestinal tumor growth.

cancer biology↗