Death-Associated Protein 3 Triggers Intrinsic Apoptosis via Miro1 Upon Inducing Intracellular Calcium Changes

Area of Science:

• Cell Biology
• Mitochondrial Biology
• Apoptosis

Background:

• Mitochondrial homeostasis is crucial for cell survival, relying on quality control mechanisms.
• Death-associated protein 3 (DAP3), a mitochondrial ribosome subunit, is involved in protein synthesis, cell death, and mitochondrial dynamics.

Purpose of the Study:

• To elucidate the role of Death-associated protein 3 (DAP3) in mediating cell death and mitochondrial fragmentation.
• To investigate the molecular mechanisms by which DAP3 influences mitochondrial calcium signaling and homeostasis.

Main Methods:

• Investigated DAP3's role in intrinsic apoptosis, mitochondrial fragmentation, membrane potential loss, ATP decline, and oxidative stress.
• Examined DAP3's interaction with Mitochondrial Rho GTPase 1 (Miro1) and the MCU complex in regulating mitochondrial calcium.
• Utilized depletion strategies for Miro1 and MCU to assess their impact on DAP3-induced cellular events.

Main Results:

• DAP3 induces cell death through intrinsic apoptosis by promoting excessive mitochondrial fragmentation, loss of mitochondrial membrane potential, ATP depletion, and oxidative stress.
• DAP3-induced mitochondrial fragmentation is mediated by Miro1, independent of canonical fusion/fission pathways.
• DAP3 enhances mitochondrial calcium accumulation via the MCU complex, reducing cytosolic Ca2+ and subsequently activating Miro1-dependent fragmentation.

Conclusions:

• Death-associated protein 3 (DAP3) plays a novel role in regulating calcium signaling and maintaining mitochondrial homeostasis.
• DAP3's function extends beyond protein synthesis to actively controlling mitochondrial integrity and cell fate.
• Targeting the DAP3-Miro1-MCU axis offers potential therapeutic strategies for conditions involving mitochondrial dysfunction.