Biology subjects

Alsina, D.

Publications and source records attributed to Alsina, D..

4 recordsLinked to original sources

bioRxiv2026

Loss of CHCHD2 and CHCHD10 reveals differential vulnerability to bioenergetic failure in cardiac and skeletal muscle

Mutations in the mitochondrial proteins CHCHD2 and CHCHD10 cause severe neurodegenerative and neuromuscular disorders, yet their physiological functions remain poorly defined. CHCHD2 and CHCHD10 localize to the mitochondrial intermembrane space, where they assemble into a high-molecular-weight complex. Here, we generated Chchd2/Chchd10 double-knockout (DKO) mice to define the in vivo role of this complex. DKO mice developed reduced lean mass, progressive muscle weakness, and oxidative phosphorylation defects in both cardiac and skeletal muscle. Despite comparable bioenergetic impairment, CHCHD2-CHCHD10 deficiency elicited tissue-specific responses distinct from those induced by the disease-associated CHCHD10 S59L mutation. The heart accumulated enlarged mitochondria with disrupted ultrastructure and underwent adaptive proteomic remodeling that preserved myocardial contractility into adulthood. By contrast, skeletal muscle exhibited limited proteomic alterations, accompanied by profound changes in lipid composition, reduced expression of the myogenic regulators, and altered myofiber size. Mechanistically, depletion of CHCHD2 and CHCHD10 in primary satellite cells impaired proliferation and myogenic differentiation, suggesting that defective postnatal myogenesis contributes to the muscle growth defect in DKO mice. Together, these findings identify the CHCHD2-CHCHD10 complex as a critical regulator of mitochondrial integrity and demonstrate that its loss drives tissue-specific defects culminating in diverse pathological outcomes.

cell biology↗

bioRxiv2026

MitoSAM-dependent lipoylation controls postnatal heart development via metabolic remodeling

The neonatal heart undergoes a rapid metabolic transition from fetal glycolysis to oxidative phosphorylation, requiring coordinated metabolic remodeling. Mechanisms driving this transition remain unclear. Here, we demonstrate that sufficient mitochondrial S-adenosylmethionine (mitoSAM), imported via the solute carrier Slc25a26, is essential for this shift by sustaining the lipoylation of 2-oxoacid dehydrogenases, critical for TCA cycle activation. Proteomic and metabolomic profiling revealed that reduced mitoSAM availability impaired lipoylation, blocking TCA cycle function and restricting nucleotide synthesis, while mitochondrial gene expression and respiratory capacity remained largely intact. In vivo EdU labeling showed persistent cardiomyocyte proliferation imposing further strain on nucleotide pools. Supplementation with medium-chain triglycerides during the suckling-to-weaning transition restored metabolic function and normalized cardiac growth and morphology. Our data reveal a critical developmental window in which mitoSAM-dependent lipoylation ensures heart maturation.

biochemistry↗

bioRxiv2024

The CHCHD2-CHCHD10 protein complex is modulated by mitochondrial dysfunction and alters lipid homeostasis in the mouse brain.

The highly conserved CHCHD2 and CHCHD10 are small mitochondrial proteins residing in the intermembrane space. Recently, mutations in the CHCHD2 and CHCHD10 genes have been linked to severe disorders, including Parkinsons disease and amyotrophic lateral sclerosis. In cultured cells, a small fraction of CHCHD2 and CHCHD10 oligomerize to form a high molecular weight complex of unknown function. Here, we generated a whole-body Chchd2 knockout mouse to investigate the in vivo role of CHCHD2 and its protein complex. We show that CHCHD2 is crucial for sustaining full motor capacity, normal striatal dopamine levels, and lipid homeostasis in the brain of adult male mice. We also demonstrate that in mouse tissues, CHCHD2 and CHCHD10 exist exclusively as a high molecular weight complex, whose levels are finely tuned under physiological conditions. In response to mitochondrial dysfunction, the abundance and size of the CHCHD2-CHCHD10 complex increases, a mechanism conserved across different tissues. Although the loss of CHCHD2 does not abolish CHCHD10 oligomerization, it enhances cell vulnerability to mitochondrial stress, suggesting that CHCHD2 is protective against mitochondrial damage. Our findings uncover the role of CHCHD2 in preserving tissue homeostasis and provide important insights into the involvement of the CHCHD2-CHCHD10 complex in human diseases.

neuroscience↗

bioRxiv2023

Inhibition of mammalian mtDNA transcription paradoxically activates liver fatty acid oxidation to reverse diet-induced hepatosteatosis and obesity

The oxidative phosphorylation (OXPHOS) system in mammalian mitochondria plays a key role in harvesting energy from ingested nutrients1, 2. Mitochondrial metabolism is very dynamic and can be reprogrammed to support both catabolic and anabolic reactions, depending on physiological demands or disease states3, 4. Rewiring of mitochondrial metabolism is intricately linked to metabolic diseases5, 6 and is also necessary to promote tumour growth7-11. Here, we demonstrate that per oral treatment with an inhibitor of mitochondrial transcription (IMT)11 shifts whole animal metabolism towards fatty acid oxidation, which, in turn, leads to rapid normalization of body weight, reversal of hepatosteatosis and restoration of glucose tolerance in mice on high-fat diet. Paradoxically, the IMT treatment causes a severe reduction of OXPHOS capacity concomitant with a marked upregulation of fatty acid oxidation in the liver, as determined by proteomics and non-targeted metabolomics analyses. The IMT treatment leads to a marked reduction of complex I, the main dehydrogenase that feeds electrons into the ubiquinone (Q) pool, whereas the levels of electron transfer flavoprotein dehydrogenase (ETF-DH) and other dehydrogenases connected to the Q pool are increased. This rewiring of metabolism caused by reduced mtDNA expression in the liver provides a novel principle for drug treatment of obesity and obesity-related pathology.

physiology↗