New research uncovers a mitochondrial quality control pathway for maintaining adequate mtDNA levels within cells

Mitochondria are small organelles within our cells that contain their own genetic material, known as mitochondrial DNA (mtDNA). mtDNA encodes 13 core subunits of the different complexes of the respiratory chain and is essential to sustain cellular metabolism and life. Only two copies of nuclear DNA (nDNA) are required to maintain cellular homeostasis, whereas the number of mtDNA molecules per cell can range from hundreds to thousands of copies depending on the cell type and cellular requirements. Indeed, mtDNA copy number (CN) is tightly regulated at the cellular level but little is known about how the recycling of mtDNA molecules occurs.

The research group of Dr. Julien Prudent at the Mitochondrial Biology Unit (University of Cambridge, Cambridge) has discovered a novel mitochondrial quality control mechanism essential for mtDNA recycling. Dr. Luis Carlos Tabara, the postdoctoral fellow leading the study, has shown that this mechanism relies on a previously poorly characterized inner mitochondrial membrane (IMM) protein called Mitochondrial Fission Protein 1 (MTFP1). The new findings demonstrate that MTFP1 detects specific IMM alterations in close association with mtDNA molecules, driving the sequestration of these mtDNA-containing areas into smaller mitochondria, that are then targeted for autophagic degradation. This mechanism is critical to maintain adequate mtDNA levels as ablation of MTFP1 impairs mtDNA degradation, leading to an increased number of mtDNA molecules per cell.

Based on this discovery, the authors employed MTFP1 inhibition as a translational approach to increase absolute mtDNA levels in cells containing mtDNA mutations. To this end, they utilized cybrid cells derived from a patient harboring a large mtDNA deletion and found that increasing mtDNA CN through MTFP1 silencing was able to partially rescue different mitochondrial alterations associated with a high mtDNA mutant load. These results provide proof of concept, suggesting that transiently targeting MTFP1 could be considered as a potential therapeutic approach for treating mitochondrial diseases.

This study, “MTFP1 controls mitochondrial fusion to regulate inner membrane quality control and maintain mtDNA levels” has been published in the journal Cell.

Legend to figure: Super-resolution Structured Illumination Microscopy (SIM) images showing small MTFP1-enriched mitochondria (marked with an anti-FLAG antibody), devoid of the outer membrane marker TOMM20, and containing or not mtDNA. Scale bar: 5 mm.

Publication reference:

MTFP1 controls mitochondrial fusion to regulate inner membrane quality control and maintain mtDNA levels.
Tábara LC, Burr SP, Frison M, Chowdhury SR, Paupe V, Nie Y, Johnson M, Villar-Azpillaga J, Viegas F, Segawa M, Anand H, Petkevicius K, Chinnery PF, Prudent J.
Cell. 2024 Jun 5:S0092-8674(24)00526-9. doi: 10.1016/j.cell.2024.05.017. Epub ahead of print. PMID: 38851188.