Biology subjects

Kwong, J. Q.

Publications and source records attributed to Kwong, J. Q..

7 recordsLinked to original sources

bioRxiv2026

Cardiomyocyte-intrinsic SLC25A1 regulates cardiac differentiation and mitochondrial function

Cardiac morphogenesis is an intricate process that requires a precise coordination between metabolic and structural maturation, but how these processes are linked remain unclear. In previous work, we identified one candidate underlying this connection: the mitochondrial citrate carrier (SLC25A1), a critical regulator of embryonic heart development. Here, using systemic and cardiomyocyte-specific Slc25a1 deletion in mice together with SLC25A1 knockout (KO) human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), we demonstrate that SLC25A1 functions cell-autonomously within cardiomyocytes to regulate differentiation, mitochondrial maturation, and ventricular morphogenesis. Transcriptomic analysis of SLC25A1-deficient hearts revealed dysregulation of gene programs regulating cardiomyocyte differentiation and mitochondrial function. Consistent with these changes, loss of SLC25A1 in developing cardiomyocytes impaired mitochondrial function and resulted in defective ventricular wall compaction in vivo. Likewise, SLC25A1 KO hiPSC-CMs exhibited defective cardiomyocyte differentiation, disorganized myofibrils, and immature mitochondrial organization and function in vitro. Together, our findings position SLC25A1 as a cardiomyocyte-intrinsic, cell-autonomous regulator that links mitochondrial citrate export to developmental gene programs, revealing a mitochondrial regulatory axis for cardiomyocyte maturation and cardiac morphogenesis that contributes to congenital heart disease.

developmental biology↗

bioRxiv2026

Suppressive Genetic Interactions Between Haploinsufficient Mitochondrial Genes Encoded in the 22q11.2 Microdeletion Locus Define Brain and Cardiac Phenotypes

Genomic copy number variations, such as the 22q11.2 microdeletion syndrome, cause pleiotropic disorders that affect diverse organ systems and disrupt neurodevelopment. Deletions of the 22q11.2 locus reduce the dosage of up to 46 protein coding genes, raising questions about the identity of haploinsufficient genes and their genetic interactions contributing to 22q11.2 phenotypes. Here, we dissect functional and molecular relationships between two genes encoded within the 22q11.2 locus: the mitochondrial ribosomal protein gene MRPL40 and the mitochondrial citrate transporter SLC25A1. We show that a MRPL40 null mutation disrupts mitochondrial translation, impairs respiration, and affects multiple components of the SLC25A1 interactome including factors required for lipid metabolism, mitochondrial ribosome subunits, and the mitochondrial RNA processing machinery. In silico coessentiality network analysis revealed correlated and anticorrelated fitness interactions linking MRPL40 and SLC25A1 to mitochondrial translation, intermediate carbon metabolism, and interferon signaling. We determined that Mrpl40-null mutations are embryonic lethal in mice, but Mrpl40-/+ mice are viable and displayed embryonic cardiac development and adult behavioral phenotypes. Similarly, Slc25a1+/- animals showed embryonic cardiac developmental defects but lacked the adult behavioral phenotypes observed in Mrpl40-/+ mice. Surprisingly, transheterozygotic Slc25a1+/-;Mrpl40-/+ mice suppressed or mitigated cardiac development, behavioral, and brain transcriptome phenotypes observed in single heterozygotic animals. These results reveal that MRPL40 and SLC25A1 are haploinsufficient genes within the 22q11.2 locus that genetically and biochemically interact to define tissue development and physiology. Our findings provide a framework for understanding the complexity and type of gene dosage interactions within the 22q11.2 deletion syndrome locus.

neuroscience↗

bioRxiv2025

Meclizine rescues cardiac function and mitochondrial ultrastructure by ATP- and glycolysis-independent mechanisms in a genetic model of mitochondrial energy dysfunction

Primary mitochondrial cardiomyopathies are an unmet clinical challenge, as there are no therapies that directly address the underlying mitochondrial dysfunction. We previously reported that the cardiomyocyte-specific deletion of the mitochondrial phosphate carrier (SLC25A3), which imports phosphate required for ATP synthesis, produces a model of mitochondrial cardiomyopathy in which total cardiac ATP levels are preserved despite defective mitochondrial ATP production. This was accompanied by increased glycolytic activity and reduced mitochondrial flux, leading us to hypothesize that pharmacologically enhancing glycolysis might be protective when the mitochondrial energy machinery is intrinsically impaired. To test this, we turned to meclizine, an FDA-approved antihistamine previously shown to shift metabolism toward glycolysis. Chronic meclizine treatment in SLC25A3-deficient mice attenuated cardiac hypertrophy, improved systolic function, and restored mitochondrial ultrastructure. Unexpectedly, meclizine suppressed glycolytic enzyme expression and reduced lactate accumulation, suggesting that meclizine does not induce a glycolytic shift in SLC25A3-deleted hearts. Instead, proteomic and functional analyses revealed preservation of mitochondrial cristae architecture via MICOS upregulation and improved NAD+/NADH homeostasis through uncoupled electron flux and NAD+ regeneration. Together, these findings identify meclizine as a clinically approved compound that promotes cardioprotection in mitochondrial disease not by driving glycolysis, but by preserving mitochondrial membrane organization and redox balance, highlighting mitochondrial quality and NAD+ redox homeostasis as therapeutic targets for primary mitochondrial cardiomyopathies.

physiology↗

bioRxiv2024

Age-dependent Changes in a Chaperone Complex in the Mouse Heart

The exquisitely organized sarcomere, the unit of contraction of striated muscle, is a stable structure with slow turnover of its components. The myosin chaperone UNC-45 and its binding partners, Hsp90 and Hsp70, are required for the initial folding of the myosin head domain and the assembly of myosin into thick filaments. There is increasing evidence that the UNC-45 system has an important role during aging to preserve sarcomere organization. Its decline may be a key factor in sarcopenia. Unlike skeletal muscle, the UNC-45 system in cardiac muscle in aging heart has not been examined extensively. Here we show that Unc45b and Hsp70 are localized to sarcomeric Z-discs in the mouse heart. We further show that during aging, there is a decline in the levels of myosin heavy chain, Unc-45b and Hsp70, but not Hsp90. While the decrease in Unc45b appears to be at the mRNA level, the decrease in the levels of myosin and Hsp70 were not at the mRNA but at the protein level. We have reported that in skeletal muscle, there is a decline in both Unc45b and Hsp90, and here we show that there is no such decline of Hsp70 in skeletal muscle. Hsp70 levels also did not decline with age in the brain or the liver. This heart-specific decrease of Hsp70 through its function as an Unc45b/Hsp70 complex might account for the age-dependent worsening of cardiomyopathies, and through Hsp70s multiple Unc-45b-independent functions, affect the folding and assembly of many other proteins in the aging heart.

cell biology↗

bioRxiv2023

Mitochondrial citrate carrier SLC25A1 is a dosage-dependent regulator of metabolic reprogramming and morphogenesis in the developing heart

The developing mammalian heart undergoes an important metabolic shift from glycolysis toward mitochondrial oxidation, such that oxidative phosphorylation defects may present with cardiac abnormalities. Here, we describe a new mechanistic link between mitochondria and cardiac morphogenesis, uncovered by studying mice with systemic loss of the mitochondrial citrate carrier SLC25A1. Slc25a1 null embryos displayed impaired growth, cardiac malformations, and aberrant mitochondrial function. Importantly, Slc25a1 heterozygous embryos, which are overtly indistinguishable from wild type, exhibited an increased frequency of these defects, suggesting Slc25a1 haploinsuffiency and dose-dependent effects. Supporting clinical relevance, we found a near-significant association between ultrarare human pathogenic SLC25A1 variants and pediatric congenital heart disease. Mechanistically, SLC25A1 may link mitochondria to transcriptional regulation of metabolism through epigenetic control of gene expression to promote metabolic remodeling in the developing heart. Collectively, this work positions SLC25A1 as a novel mitochondrial regulator of ventricular morphogenesis and cardiac metabolic maturation and suggests a role in congenital heart disease.

developmental biology↗

bioRxiv2021

Mitochondrial energy dysfunction induces remodeling of the cardiac mitochondrial protein acylome

Mitochondria are increasingly recognized as signaling organelles because, under conditions of stress, mitochondria can trigger various signaling pathways to coordinate the cells response. The specific pathway(s) engaged by mitochondria in response to defects in mitochondrial energy production in vivo and in high-energy tissues like the heart are not fully understood. Here, we investigated cardiac pathways activated in response to mitochondrial energy dysfunction by studying mice with cardiomyocyte-specific loss of the mitochondrial phosphate carrier (SLC25A3), an established model that develops cardiomyopathy as a result of defective mitochondrial ATP synthesis. In heart tissue from these mice, mitochondrial energy dysfunction induced a striking pattern of acylome remodeling, with significantly increased post-translational acetylation and malonylation. Mass spectrometry-based proteomics further revealed that energy dysfunction-induced remodeling of the acetylome and malonylome preferentially impacts mitochondrial proteins. Acetylation and malonylation modified a highly interconnected interactome of mitochondrial proteins, and both modifications were present on the enzyme isocitrate dehydrogenase 2 (IDH2). Intriguingly, IDH2 activity was enhanced in SLC25A3-deleted mitochondria, and further study of IDH2 sites targeted by both acetylation and malonylation revealed that these modifications can have site-specific and distinct functional effects. Finally, we uncovered a novel crosstalk between the two modifications, whereby mitochondrial energy dysfunction-induced acetylation of sirtuin 5 (SIRT5), inhibited its function. Because SIRT5 is a mitochondrial deacylase with demalonylase activity, this finding suggests that acetylation can modulate the malonylome. Together, our results position acylations as an arm of the mitochondrial response to energy dysfunction and suggest a mechanism by which focal disruption to the mitochondrial energy production machinery can have an expanded impact on global mitochondrial function.

cell biology↗

bioRxiv2020

Mitochondrial functional resilience after TFAM ablation in adult cardiomyocytes

The adult heart is a terminally differentiated tissue that depends on mitochondria for its energy supply. Respiratory chain energy supply deficits due to alterations in the mitochondrial genome (mtDNA) or in nuclear genome (nDNA)-encoded mtDNA regulators are associated with cardiac pathologies ranging from primary mitochondrial cardiomyopathies to heart failure. Mitochondrial transcription factor A (TFAM) is an nDNA-encoded regulator of mtDNA transcription, replication, and maintenance. Insufficiency of this protein in embryonic and postnatal cardiomyocytes causes cardiomyopathy and/or lethality, establishing TFAM as indispensable to the developing heart; its role in adult tissue has been inferred from these findings. Here, we provide evidence that challenges this long-standing paradigm using Tfam ablation in the adult heart. Unexpectedly, loss of Tfam in adult cardiomyocytes resulted in a prolonged period of functional resilience characterized by preserved mtDNA content, mitochondrial function, and cardiac function despite mitochondrial structural alterations and decreased transcript abundance. Remarkably, TFAM protein levels did not directly dictate mtDNA content in the adult heart, and mitochondrial translation was preserved with acute TFAM inactivation, suggesting a mechanism whereby respiratory chain assembly and function can be sustained, which we term functional resilience. Finally, long-term Tfam inactivation induced a coordinated downregulation of the core mtDNA transcription and replication machinery that ultimately resulted in mitochondrial dysfunction and cardiomyopathy. Taken together, adult-onset cardiomyocyte-specific Tfam inactivation reveals a striking resilience of the adult heart to acute insults to mtDNA regulatory mechanisms and provides insight into critical differences between the developing versus differentiated heart.

cell biology↗