SYVN1-Mediated Degradation of SHMT2 Drives Tubular Injury Progression via Metabolic Reprogramming

Area of Science:

• Biochemistry
• Molecular Biology
• Nephrology

Background:

• Serine hydroxymethyltransferase 2 (SHMT2) is crucial for one-carbon metabolism.
• Its role and regulation in acute kidney injury (AKI) are not well understood.

Purpose of the Study:

• To investigate SHMT2 downregulation in AKI.
• To elucidate the molecular mechanisms driving SHMT2 regulation and its impact on kidney injury.

Main Methods:

• Murine models of AKI (ischemia-reperfusion, unilateral ureteral obstruction).
• In vitro studies using human proximal tubular HK-2 cells.
• Genetic (shRNA) and pharmacological (SHIN1) inhibition of SHMT2.
• Overexpression of E3 ubiquitin ligase synoviolin (SYVN1).

Main Results:

• SHMT2 expression was significantly reduced in AKI kidneys, inversely correlating with injury severity.
• SHMT2 inhibition exacerbated tubular damage, mitochondrial dysfunction, oxidative stress, and metabolic impairment.
• SYVN1 directly interacted with SHMT2, promoting its proteasomal degradation via ubiquitination.
• SYVN1-mediated SHMT2 degradation contributed to AKI progression through metabolic reprogramming.

Conclusions:

• SHMT2 downregulation is a pathogenic mechanism in AKI.
• The SYVN1/SHMT2 axis represents a novel pathway in kidney injury.
• Targeting the SYVN1/SHMT2 interaction may offer a therapeutic strategy for AKI.