Adaptive mechanisms in pancreatic islets counteract mitochondrial dysfunction in Barth syndrome

Abstract

Aims/hypothesis Barth syndrome is a mitochondrial disorder caused by Tafazzin (TAZ) mutations, which impair cardiolipin remodelling and contribute to systemic metabolic alterations. While islet dysfunction has been implicated in Barth syndrome, its underlying mechanisms remain unknown. We aimed to determine how Tafazzin (Taz) deficiency affects mouse pancreatic islet metabolism and hormone secretion, and whether systemic signals, such as circulating factors, modulate these effects in vivo. In vivo and in vitro models were used to separate direct islet effects from systemic influences of Taz deficiency. Methods We used a mouse model of global Taz knockdown (Taz-KD) and combined in vivo and in vitro approaches to assess pancreatic islet metabolism, morphology and hormone secretion. Islet function was evaluated under basal and glucotoxic conditions. Transcriptomic profiling was performed to identify gene expression changes in isolated islets from Taz-KD mice and following in vitro Taz-KD. Additionally, we examined the role of the circulating factor fibroblast growth factor 21 (FGF-21) in modulating islet function. Results Despite impaired cardiolipin remodelling, pancreatic islets from Taz-KD mice maintained insulin secretion, sup ported by compensatory mechanisms such as increased glucose uptake, expanded mitochondrial volume and increased metabolic parameters. In addition, alpha cell mass and glucagon secretion were significantly increased in Taz-KD islets. These islet-specific adaptations occurred alongside improved whole-body glucose tolerance, elevated circulating FGF-21 levels and enhanced glucose uptake in brown adipose tissue. In contrast, in vitro Taz-KD led to impaired islet function and reduced insulin secretion. Transcriptomic analysis revealed distinct gene expression patterns between in vivo and in vitro Taz-KD models. While in vivo upregulation of genes related to N-acetylglucosamine biosynthesis and O-GlcNAcylation were related to compensatory mechanisms, in vitro Taz-KD affected, among others, the MAPK pathway, contributing to islet dysfunction. Notably, islet incubation with FGF-21 was able to restore insulin secretion after in vitro Taz-KD. Conclusions/interpretation Our findings demonstrate that while Taz and cardiolipin remodelling are essential for beta cell physiology, systemic and islet-specific compensatory mechanisms preserve insulin secretion in vivo in Taz-KD mice, alongside increased glucagon secretion. These adaptations probably contribute to the altered metabolic phenotype observed in Barth syndrome and highlight a potential role for hormones and circulating factors such as FGF-21 in maintaining islet function and glucose homeostasis.