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Assessment of Mitochondrial Functions and Cell Viability in Renal Cells Overexpressing Protein Kinase C Isozymes
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Mitofusin2 Ameliorated Endoplasmic Reticulum Stress and Mitochondrial Reactive Oxygen Species Through Maintaining

Yu-Ting Liu1, Hao Zhang1, Shao-Bin Duan2

  • 1Department of Nephrology, The Third Xiangya Hospital, The Critical Kidney Disease Research Center, Central South University, Changsha, China.

Antioxidants & Redox Signaling
|April 13, 2023
PubMed

Insights

Mitofusin2 (Mfn2) loss disrupts mitochondria-associated endoplasmic reticulum membrane (MAM) integrity, worsening cisplatin-induced acute kidney injury (CP-AKI). Restoring Mfn2 protects against cellular injury by regulating endoplasmic reticulum (ER) stress and mitochondrial ROS.

Area of Science:

  • Cell Biology
  • Nephrology
  • Molecular Medicine

Background:

  • Cisplatin-induced acute kidney injury (CP-AKI) involves mitochondrial dysfunction and endoplasmic reticulum (ER) stress.
  • Mitochondria-associated ER membrane (MAM) integrity is crucial for cellular homeostasis.
  • The role of Mitofusin2 (Mfn2) in CP-AKI, particularly its connection to MAMs and ER stress, remains unclear.

Purpose of the Study:

  • To investigate the regulatory role of Mfn2 in maintaining MAM integrity and mitigating cellular injury in CP-AKI.
  • To elucidate the molecular mechanisms linking Mfn2, MAMs, ER stress, and mitochondrial reactive oxygen species (ROS) in CP-AKI.

Main Methods:

  • Mice models of CP-AKI and in vitro cell cultures (BUMPT, HK-2) were used.
  • Mfn2 expression, MAM integrity, ER stress markers (IRE1, PERK), mitochondrial ROS, and apoptosis were assessed.
  • Mfn2 plasmid transfection, Mfn2 siRNA, AMPK activator (AICAR), and ER stress inhibitor (4-PBA) were employed.

Main Results:

  • CP-AKI mice and cells showed decreased Mfn2, impaired MAM integrity, elevated ER stress, and increased ROS and apoptosis.
  • Mfn2 overexpression protected against CP-induced cellular injury, reduced ER stress, and restored MAM integrity.
  • Mfn2 knockdown exacerbated ER stress and MAM disruption under cisplatin treatment.
  • Mfn2 directly interacted with ER stress mediators PERK and IRE1.

Conclusions:

  • Mfn2 downregulation is a key event in CP-AKI, leading to MAM disruption, ER stress, and tubular cell apoptosis.
  • The Mfn2-MAMs pathway plays a critical protective role against CP-AKI.
  • Targeting the Mfn2-MAMs pathway represents a promising therapeutic strategy for CP-AKI.
Keywords:
CP-AKIMAMsMfn2endoplasmic reticulummitochondrial

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