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SLC25A42 encodes the mitochondrial coenzyme A (CoA) transporter localized at the inner mitochondrial membrane. SLC25A42 deficiency leads to a congenital disease with a heterogeneous clinical presentation, including myopathy, developmental delay, lactic acidosis, and encephalopathy. Twenty-one patients have been described so far. In the current study, we report on the identification of new biallelic variants in SLC25A42 in three siblings. Patients presented with symmetrical T2 hyperintensity of the putamen with minor volume depression at the brain MRI, elevated lactate, reduced oxygen consumption rates in muscle and fibroblasts, and reduced CoA levels in fibroblasts. Administration of pantothenic acid led to clinical stabilization and increased CoA levels in fibroblasts, thus confirming a role for SLC25A42 in energy metabolism and CoA homeostasis., Competing Interests: Katharina Heckmann, Arcangela Iuso, Marianne Grueneberg, Anja Seelhoefer, Stefan Rust, Janine Reunert, Giuseppe Fiermonte, Eleonora Paradies, Carmen Piazolla, Mannil Manoj and Thorsten Marquardt declare that they have no conflict of interest., (© 2024 The Author(s). JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.)

The oncogenic KRAS mutation has a critical role in the initiation of human pancreatic ductal adenocarcinoma (PDAC) since it rewires glutamine metabolism to increase reduced nicotinamide adenine dinucleotide phosphate (NADPH) production, balancing cellular redox homeostasis with macromolecular synthesis 1,2 . Mitochondrial glutamine-derived aspartate must be transported into the cytosol to generate metabolic precursors for NADPH production 2 . The mitochondrial transporter responsible for this aspartate efflux has remained elusive. Here, we show that mitochondrial uncoupling protein 2 (UCP2) catalyses this transport and promotes tumour growth. UCP2-silenced KRAS mut cell lines display decreased glutaminolysis, lower NADPH/NADP + and glutathione/glutathione disulfide ratios and higher reactive oxygen species levels compared to wild-type counterparts. UCP2 silencing reduces glutaminolysis also in KRAS WT PDAC cells but does not affect their redox homeostasis or proliferation rates. In vitro and in vivo, UCP2 silencing strongly suppresses KRAS mut PDAC cell growth. Collectively, these results demonstrate that UCP2 plays a vital role in PDAC, since its aspartate transport activity connects the mitochondrial and cytosolic reactions necessary for KRAS mut rewired glutamine metabolism 2 , and thus it should be considered a key metabolic target for the treatment of this refractory tumour.

Several ATP-depending reactions take place in the endoplasmic reticulum (ER). Although in Saccharomyces cerevisiae ER the existence of a Sac1p-dependent ATP transport system was already known, its direct involvement in ATP transport was excluded. Here we report an extensive biochemical characterization of a partially purified adenine nucleotide transport system (ANTS) not dependent on Sac1p. Highly purified ER membranes from the wild-type and Δsac1 yeast strains reconstituted into liposomes transported ATP with the same efficiency. A chromatography on hydroxyapatite was used to partially purify ANTS from Δsac1 ER extract. The two ANTS-enriched transport activity eluted fractions showed essentially the presence of four bands, one having an apparent MW of 56 kDa, similar to that observed for ANTS identified in rat liver ER. The two fractions reconstituted into liposomes efficiently transported, by a strict counter-exchange mechanism, ATP and ADP. ATP transport was saturable with a Km of 0.28 mM. The ATP/ADP exchange mechanism and the kinetic constants suggest that the main physiological role of ANTS is to catalyse the transport of ATP into ER, where it is used in several energy-requiring reactions and to export back to the cytosol the ADP produced.