Biology subjects

Baker, Z. N.

Publications and source records attributed to Baker, Z. N..

5 recordsLinked to original sources

bioRxiv2026

Pathogenic variants of the mitochondrial copper chaperones SCO1 and SCO2 reshape their respective interactomes and disrupt cellular phospholipid metabolism

SCO1 and SCO2 are required for copper delivery to COX2, a copper-containing subunit of cytochrome c oxidase (COX), yet how mutations in these genes cause distinct, tissue-specific forms of human disease remains poorly understood. To gain further insight into the molecular underpinnings of this clinical heterogeneity, we used BioID to map the interactomes of four pathogenic SCO variants (SCO1 G132S, SCO1 P174L, SCO1 M294V and SCO2 E140K) and the wild-type proteins. While this approach identified many proteins common to both wild-type neighbourhoods, several potential interacting partners unique to each SCO protein were also observed that were consistent with their known roles in COX assembly. Follow-up analyses revealed that SCO1 interacts with COX16 and that this interaction is stabilized within the membrane by a coiled-coil helix-helix interface, with the soluble C-terminal region of COX16 physically bridging SCO1 and COX2 within a ternary complex to facilitate copper delivery. We further observed that COX16 abundance is relatively low in the brain and its association with SCO1 is most severely impaired by the M294V substitution associated with a fatal encephalopathy. Intriguingly, our BioID analyses also detected significant enrichment in each SCO neighbourhood for biosynthetic enzymes and lipases critical to phospholipid metabolism and found that the affinity for these candidate interactors was uniquely perturbed by various pathogenic variants of SCO1 and SCO2. Collectively, our data emphasize the potential of proximity labelling to further define the molecular roles of disease-causing variants that perturb mitochondrial function and suggest that SCO proteins impinge upon phospholipid metabolism.

molecular biology↗

bioRxiv2025

Fmp30 is a phosphatidylinositol hydrolase that regulates CoQ biosynthesis

Coenzyme Q (CoQ, ubiquinone) is a redox-active isoprene lipid that supports fundamental enzymatic and antioxidant roles in mitochondria and beyond. Despite CoQs importance in organismal health and disease, the mechanisms that regulate its biosynthetic pathway remain elusive. Motivated by this, we mined S. cerevisiae multiomics datasets for genes whose disruptions alter CoQ levels and discovered the gene FMP30 as an unexpected negative regulator of CoQ biosynthesis. Loss of FMP30 results in elevated complex Q protein abundance, increased number and intensity of CoQ domains, and ultimately enhanced CoQ biosynthetic flux. We demonstrate that Fmp30, a member of the metallo-{beta}-lactamase super family, displays phospholipase type D activity toward phosphatidylinositol and phosphoinositides, and that its deletion causes marked elevation of these lipid species in purified mitochondria. Collectively, our work nominates Fmp30 as a novel regulator linking mitochondrial phospholipid metabolism to CoQ biosynthesis.

biochemistry↗

bioRxiv2025

Uridine-sensitized screening identifies genes and metabolic regulators of nucleotide synthesis

Nucleotides are essential for nucleic acid synthesis, signaling, and metabolism, and can be synthesized de novo or through salvage. Rapidly proliferating cells require large amounts of nucleotides, making nucleotide metabolism a widely exploited target for cancer therapy. However, resistance frequently emerges, highlighting the need for a deeper understanding of nucleotide regulation. Here, we harness uridine salvage and CRISPR-Cas9 screening to reveal regulators of de novo pyrimidine synthesis. We identify several factors and report that pyrimidine synthesis can continue in the absence of coenzyme Q (CoQ), the canonical electron acceptor in de novo synthesis. We further investigate NUDT5 and report its conserved interaction with PPAT, the rate-limiting enzyme in purine synthesis. We show that in the absence of NUDT5, hyperactive purine synthesis siphons the phosphoribosyl pyrophosphate (PRPP) pool at the expense of pyrimidine synthesis, promoting resistance to chemotherapy. Intriguingly, the interaction between NUDT5 and PPAT appears to be disrupted by PRPP, highlighting intricate allosteric regulation. Our findings reveal a fundamental mechanism for maintaining nucleotide balance and position NUDT5 as a potential biomarker for predicting resistance to chemotherapy.

biochemistry↗

bioRxiv2024

ACAD10 and ACAD11 enable mammalian 4-hydroxy acid lipid catabolism

Fatty acid {beta}-oxidation (FAO) is a central catabolic pathway with broad implications for organismal health. However, various fatty acids are largely incompatible with standard FAO machinery until they are modified by other enzymes. Included among these are the 4-hydroxy acids (4-HAs)--fatty acids hydroxylated at the 4 ({gamma}) position--which can be provided from dietary intake, lipid peroxidation, and certain drugs of abuse. Here, we reveal that two atypical and poorly characterized acyl-CoA dehydrogenases (ACADs), ACAD10 and ACAD11, drive 4-HA catabolism in mice. Unlike other ACADs, ACAD10 and ACAD11 feature kinase domains N-terminal to their ACAD domains that phosphorylate the 4-OH position as a requisite step in the conversion of 4-hydroxyacyl-CoAs into 2-enoyl-CoAs--conventional FAO intermediates. Our ACAD11 cryo-EM structure and molecular modeling reveal a unique binding pocket capable of accommodating this phosphorylated intermediate. We further show that ACAD10 is mitochondrial and necessary for catabolizing shorter-chain 4-HAs, whereas ACAD11 is peroxisomal and enables longer-chain 4-HA catabolism. Mice lacking ACAD11 accumulate 4-HAs in their plasma while comparable 3- and 5-hydroxy acids remain unchanged. Collectively, this work defines ACAD10 and ACAD11 as the primary gatekeepers of mammalian 4-HA catabolism and sets the stage for broader investigations into the ramifications of aberrant 4-HA metabolism in human health and disease.

biochemistry↗

bioRxiv2021

Mitochondrial dysfunction triggers secretion of the immunosuppressive factor α-fetoprotein

Signaling circuits crucial to systemic physiology are widespread, yet uncovering their molecular underpinnings remains a barrier to understanding the etiology of many metabolic disorders. Here, we identify a copper-linked signaling circuit activated by disruption of mitochondrial function in the murine liver or heart that results in atrophy of the spleen and thymus and causes a peripheral white blood cell deficiency. We demonstrate that the leukopenia is caused by -fetoprotein, which requires copper and the cell surface receptor CCR5 to promote white blood cell death. We further show that -fetoprotein expression is upregulated in several cell types upon inhibition of oxidative phosphorylation, including a muscle cell model of Barth syndrome. Collectively, our data argue that -fetoprotein secreted by bioenergetically stressed tissue suppresses the immune system, an effect which may explain the recurrent infections that are observed in a subset of mitochondrial diseases or in other disorders with mitochondrial involvement.

cell biology↗