Intrinsic and extrinsic regulation of rhabdomyolysis susceptibility by Tango2

Abstract

Rhabdomyolysis is a clinical emergency characterized by severe muscle damage, resulting in the release of intracellular muscle components, which leads to myoglobinuria and, in severe cases, acute kidney failure. Rhabdomyolysis is caused by genetic factors linked to increased disease susceptibility in response to extrinsic triggers. Recessive mutations in TANGO2 result in episodic rhabdomyolysis, metabolic crises, encephalopathy, and cardiac arrhythmia. The underlying mechanism contributing to disease onset in response to specific triggers remains unclear. To address these challenges, we created a zebrafish model of Tango2 deficiency. Here we demonstrate that the loss of Tango2 in zebrafish results in growth defects, early lethality, and increased susceptibility of skeletal muscle defects in response to extrinsic triggers similar to TANGO2 patients. Using lipidomics, we identified alterations in the glycerolipid pathway in tango2 mutants which is critical for membrane stability and energy balance. Therefore, these studies provide insight into key disease processes in Tango2 deficiency and have increased our understanding of the impacts of specific defects on predisposition to environmental triggers in TANGO2-related disorders.

TANGO2-related rhabdomyolysis symptoms are associated with abnormal autophagy functioning

“…TRAPPopathies due to TRAPPC11 or TRAPPC12 mutations, that present neurological features associated with possible rhabdomyolysis, display a defect in both trafficking machinery between the ER and the Golgi apparatus and autophagy [56][57][58] , similarly to TANGO2 disease. On the other hand, recent advances in the understanding of TANGO2 disease point towards defects in lipid metabolism with decreased overall abundances of membrane and cellular lipids 13,15,16,19 . Indeed, two recent papers have shown abnormal lipid profiles in TANGO2 models, with reduced levels of phosphatidic acid and increased levels of its unacetylated precursor, lysophosphatidic acid, in Hep2g cells 19 , and decreased phosphatidylcholine and triglycerides in zebrafish 15 .…”

“…TANGO2 function is poorly understood but has been reported to be required for endoplasmic reticulum (ER) -Golgi 1, 12-15 , and haem 16 transports. Depletion of TANGO2 results in slowed cargo movements between the ER and the Golgi in patient's fibroblasts 14 , ER and Golgi fusion in Drosophila cells 13 , and/or abnormal ER/Golgi morphology in different models 1,12,[14][15][16] . However, abnormal ER morphology in patients' cells has not been systematically observed 1,5 .…”

“…RM can be triggered by fasting and infections, but also by exposure to cold or heat. TANGO2 function is poorly understood but has been reported to be required for endoplasmic reticulum (ER) - Golgi 1, 12–15 , and haem 16 transports. Depletion of TANGO2 results in slowed cargo movements between the ER and the Golgi in patient’s fibroblasts 14 , ER and Golgi fusion in Drosophila cells 13 , and/or abnormal ER/Golgi morphology in different models 1, 12, 14–16 .…”

“…However, abnormal ER morphology in patients’ cells has not been systematically observed 1, 5 . On the other hand, besides the vicinity of the ER 12, 15 , TANGO2 is mainly cytosolic 7 where it has been shown to partially localize to mitochondria 2, 9, 14, 17, 18 and lipid droplets 19 . Importantly, the overall abundance of major membrane and cellular lipids synthesized through ER/sarcoplasmic reticulum is significantly decreased in tango2 mutant zebrafish at the basal level in the absence of any external trigger 15 , and in Hep2g cells 19 .…”

“…On the other hand, besides the vicinity of the ER 12, 15 , TANGO2 is mainly cytosolic 7 where it has been shown to partially localize to mitochondria 2, 9, 14, 17, 18 and lipid droplets 19 . Importantly, the overall abundance of major membrane and cellular lipids synthesized through ER/sarcoplasmic reticulum is significantly decreased in tango2 mutant zebrafish at the basal level in the absence of any external trigger 15 , and in Hep2g cells 19 . Plasma and fibroblasts from TANGO2 patients exhibit abnormal accumulation of fatty acids and/or a defect in palmitate-dependent oxygen consumption suggesting impairment in mitochondrial fatty acid oxidation 2, 9, 12, 17 .…”