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PPA2 activates MTFP1-DNM1L fission signaling to govern mitochondrial proliferation and mitophagy

Soumya Ranjan Mishra1, Priyadarshni Mishra1, Kewal Kumar Mahapatra1

  • 1Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela, India.

Autophagy
|August 28, 2025
PubMed

Insights

Inorganic pyrophosphatase PPA2 activates mitochondrial fission signaling, promoting mitochondrial proliferation or mitophagy. PPA2, interacting with MTFP1, is crucial for maintaining mitochondrial homeostasis.

Area of Science:

  • Cell Biology
  • Mitochondrial Dynamics
  • Biochemistry

Background:

  • Mitochondrial function is vital for cellular health.
  • Mitochondrial fission and fusion dynamics are critical for maintaining homeostasis.
  • The role of inorganic pyrophosphatase PPA2 in mitochondrial dynamics is largely unknown.

Purpose of the Study:

  • To elucidate the role of inorganic pyrophosphatase PPA2 in regulating mitochondrial fission.
  • To investigate the molecular mechanisms by which PPA2 controls mitochondrial fission signaling.
  • To determine PPA2's contribution to mitochondrial proliferation and mitophagy.

Main Methods:

  • Overexpression and knockdown of PPA2 and MTFP1.
  • Analysis of mitochondrial translocation of phosphorylated DNM1L S616.
  • Assessment of mitochondrial fission sites and dynamics.
  • Investigation of PPA2 interaction with MTFP1 and its role in mitophagy.

Main Results:

  • PPA2 overexpression promotes mitochondrial fission by enhancing phosphorylated DNM1L S616 translocation.
  • PPA2 interacts with MTFP1 to activate fission signaling; MTFP1 knockdown abrogates PPA2-induced fission.
  • PPA2 directs midzone fission via MFF-DNM1L for proliferation and peripheral fission via FIS1-DNM1L for mitophagy during stress.
  • PPA2 utilizes MTFP1's LIR for mitophagy-mediated clearance of damaged mitochondria.

Conclusions:

  • PPA2 is a key activator of mitochondrial fission signaling through the MTFP1-DNM1L pathway.
  • PPA2 dictates the site of mitochondrial fission, influencing both proliferation and mitophagy.
  • PPA2 plays an essential role in maintaining mitochondrial homeostasis through regulated fission events.
Keywords:
MTFP1MitochondriaPPA2mitochondrial fissionmitophagy

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