Miro1 Protects Against Acute Kidney Injury Through Modulating Mitochondrial Homeostasis via Interaction With Sirt6

Area of Science:

• Nephrology
• Mitochondrial Biology
• Molecular Medicine

Background:

• Acute kidney injury (AKI) is a global health concern with limited treatment options.
• Mitochondrial dysfunction is a key factor in AKI pathogenesis, highlighting the need for mitochondrial protective strategies.
• The role of Miro1, a regulator of mitochondrial dynamics, in AKI is currently unknown.

Purpose of the Study:

• To investigate the role of Miro1 in AKI.
• To explore the regulatory mechanism of Miro1 in renal tubular cells.
• To identify potential therapeutic targets for AKI.

Main Methods:

• Analysis of Miro1 expression in human AKI patient samples and murine AKI models.
• Functional studies assessing the impact of Miro1 loss and overexpression on tubular cell injury and mitochondrial function.
• Identification and characterization of Miro1 interacting proteins, including Sirt6.
• Investigation of the Sirt6-Miro1 interaction and its effect on Miro1 stability and AKI pathogenesis.

Main Results:

• Miro1 expression was significantly decreased in renal tubular cells of AKI patients and murine models.
• Miro1 deficiency exacerbated kidney injury and mitochondrial dysfunction, while Miro1 overexpression conferred protection.
• Sirt6 was identified as a novel interacting partner of Miro1, deacetylating it at K182 to prevent degradation.
• Sirt6 activation protected against AKI by stabilizing Miro1, whereas Sirt6 inhibition worsened kidney injury.

Conclusions:

• The Sirt6-Miro1 axis represents a novel protective mechanism in AKI.
• Sirt6 stabilizes Miro1 through deacetylation, preserving mitochondrial homeostasis and mitigating kidney injury.
• Targeting the Sirt6-Miro1 pathway offers a promising therapeutic strategy for AKI intervention.