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NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy

V E Kagan1, J Jiang1, Z Huang1

  • 1Department of Environmental and Occupational Health, Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA, USA.

Cell Death and Differentiation
|January 9, 2016
PubMed

Insights

NDPK-D protein facilitates cardiolipin externalization, a key signal for mitophagy, essential for cellular homeostasis. This discovery uncovers the machinery behind mitochondrial degradation.

Area of Science:

  • Cell Biology
  • Mitochondrial Biology
  • Autophagy Research

Background:

  • Mitophagy is crucial for maintaining cellular health and homeostasis.
  • Cardiolipin (CL) externalization to the outer mitochondrial membrane (OMM) serves as a signal for mitophagy.
  • The molecular machinery responsible for CL translocation remains unidentified.

Purpose of the Study:

  • To identify the protein responsible for cardiolipin translocation during mitophagy.
  • To elucidate the role of NDPK-D in CL externalization and mitophagy.
  • To investigate the connection between mitochondrial dynamics and mitophagy.

Main Methods:

  • Utilized RNAi knockdown to assess the function of NDPK-D in mitophagy.
  • Employed a cardiolipin-binding mutant of NDPK-D to study its activity.
  • Applied in situ proximity ligation assay (PLA) to examine protein interactions.
  • Investigated mitophagy induction using CCCP, rotenone, and 6-hydroxydopamine in various cell lines.

Main Results:

  • NDPK-D (NM23-H4) was identified as a hexameric protein that binds cardiolipin and facilitates its transfer to the OMM.
  • CCCP-induced CL externalization and mitophagy were reduced upon NDPK-D knockdown.
  • A non-CL-binding NDPK-D mutant failed to promote mitophagy.
  • NDPK-D's mitophagy-inducing activity was linked to OPA1, suggesting a role for mitochondrial fission-fusion dynamics.

Conclusions:

  • NDPK-D is a critical component of the CL-translocating machinery required for mitophagy.
  • The study reveals a novel mechanism for regulating mitophagy through CL externalization.
  • Mitochondrial dynamics, involving OPA1, are implicated in the regulation of NDPK-D-mediated mitophagy.

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