Background: Mitochondrial dynamics are essential for maintaining cellular function under metabolic stress. However, their role in colon cancer's response to glucose deprivation remains poorly understood.

Methods: The role of the mitochondrial protein MTFR1 in colon cancer proliferation was evaluated using CCK-8 and colony formation assays. Mass spectrometry identified MTFR1-interacting proteins and phosphorylation sites. Mitochondrial morphology was examined with Mitotracker staining, and mitochondrial function was evaluated using MitoSOX, JC-1 staining, and the Seahorse cell mitochondrial stress test.

Results: We observed that MTFR1 is highly expressed in colon cancer cells and interacts with NEK1 under glucose deprivation. This interaction induces phosphorylation of MTFR1 at serine 119, which promotes mitochondrial fusion and supports mitochondrial function. Consequently, enhanced oxidative phosphorylation improves cellular tolerance to glucose deprivation.

Conclusions: Our findings highlight the importance of MTFR1 in modulating mitochondrial dynamics and its potential impact on colon cancer cell survival under metabolic stress. These results suggest that MTFR1 serine 119 could be a key regulator of colon cancer cell metabolism and a potential therapeutic target for enhancing cancer cell response to metabolic challenges.

Keywords: Colorectal cancer; Glucose deprivation; MTFR1; Mitochondrial fusion; NEK1.

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