Carlein, C.; Hoffmann, M. D.; Amaral, A. G.; Bickelmann, C.; Lotfinia, A.; de Selliers, L.-A.; Audouze-Chaud, J.; Wrublewsky, S.; Lauterbach, M. A.; von der Malsburg, K.; van der Laan, M.; Bozem, M.; Hoth, M.; Gilon, P.; Ravier, M.; Morgan, B.; Ampofo, E.; Maack, C.; Prates Roma, L.

Barth syndrome is a multisystem genetic disorder caused by mutation in TAFAZZIN, a gene that encodes a phospholipid:lysophospholipid transacylase important for cardiolipin remodeling. Barth Syndrome patients suffer from a number of symptoms including early heart failure, fatigue, and systemic metabolic alterations, including hypoglycemia. The endocrine pancreas is central to glucose homeostasis, however, the impact of defective cardiolipin remodeling on pancreatic islet function and the consequences for systemic metabolism is unclear. Surprisingly, in a mouse model with global TAFAZZIN knockdown, we observed improved glucose tolerance compared to wildtype littermates. We show that pancreatic islet metabolism and secretory function is robustly maintained through various compensatory mechanisms including increased glucose uptake and increased mitochondrial volume. Transcriptomics analyses revealed increased expression of genes encoding proteins involved in N-acetylglucosamine synthesis and protein O-linked N-acetylglucosaminylation. These pathways might provide a molecular mechanism for coupling metabolic changes to mitochondrial volume regulation.