Abstract

Diabetic-associated cognitive dysfunction (DACD) is a severe complication of diabetes characterized by mitochondrial failure in hippocampal neurons, yet its precise molecular drivers remain poorly understood. Here, hydroxysteroid dehydrogenase-like 2 (HSDL2) was identified as a key mitochondrial-related protein significantly upregulated in DACD models. Knockdown of HSDL2 alleviated cognitive impairment, synaptic loss, and neuronal apoptosis in DACD mice. Mechanistic investigations revealed that HSDL2 promoted mitochondrial dysfunction and neuronal apoptosis by downregulating TNF receptor-associated protein 1 (TRAP1). Furthermore, HSDL2 was identified as a novel substrate of the desuccinylase sirtuin 5 (SIRT5). SIRT5 mediated HSDL2 desuccinylation at the K42 site to stabilize its protein, leading to its upregulation. Importantly, SIRT5 was upregulated in DACD, and its knockdown mitigated hippocampal damage and cognitive dysfunction. This study unveiled a novel SIRT5/HSDL2/TRAP1 axis in DACD pathogenesis, wherein SIRT5 upregulation drove HSDL2 desuccinylation and stabilization, ultimately promoting mitochondrial dysfunction and cognitive decline via downregulation of TRAP1.