The inner mitochondrial membrane fission protein MTP18 serves as a mitophagy receptor to prevent apoptosis in oral cancer.

Autor:	Panigrahi DP; Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha, 769008, India., Praharaj PP; Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha, 769008, India., Behera BP; Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha, 769008, India., Patra S; Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha, 769008, India., Patil S; College of Dental Medicine, Roseman University of Health Sciences, South Jordan, UT 84095, USA.; Centre of Molecular Medicine and Diagnostics (COMManD), Saveetha Dental College & Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai-600 077, India., Patro BS; Bio-Organic Division, Bhabha Atomic Research Centre, Mumbai-400085, India., Bhutia SK; Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha, 769008, India.
Jazyk:	angličtina
Zdroj:	Journal of cell science [J Cell Sci] 2023 Jul 01; Vol. 136 (13). Date of Electronic Publication: 2023 Jul 11.
DOI:	10.1242/jcs.259986
Abstrakt:	MTP18 (also known as MTFP1), an inner mitochondrial membrane protein, plays a vital role in maintaining mitochondrial morphology by regulating mitochondrial fission. Here, we found that MTP18 functions as a mitophagy receptor that targets dysfunctional mitochondria into autophagosomes for elimination. Interestingly, MTP18 interacts with members of the LC3 (also known as MAP1LC3) family through its LC3-interacting region (LIR) to induce mitochondrial autophagy. Mutation in the LIR motif (mLIR) inhibited that interaction, thus suppressing mitophagy. Moreover, Parkin or PINK1 deficiency abrogated mitophagy in MTP18-overexpressing human oral cancer-derived FaDu cells. Upon exposure to the mitochondrial oxidative phosphorylation uncoupler CCCP, MTP18[mLIR]-FaDu cells showed decreased TOM20 levels without affecting COX IV levels. Conversely, loss of Parkin or PINK1 resulted in inhibition of TOM20 and COX IV degradation in MTP18[mLIR]-FaDu cells exposed to CCCP, establishing Parkin-mediated proteasomal degradation of outer mitochondrial membrane as essential for effective mitophagy. We also found that MTP18 provides a survival advantage to oral cancer cells exposed to cellular stress and that inhibition of MTP18-dependent mitophagy induced cell death in oral cancer cells. These findings demonstrate that MTP18 is a novel mitophagy receptor and that MTP18-dependent mitophagy has pathophysiologic implications for oral cancer progression, indicating inhibition of MTP18-mitophagy could thus be a promising cancer therapy strategy. Competing Interests: Competing interests The authors declare no competing or financial interests. (© 2023. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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