Mitochondrial dynamics modulation by IF1 in cancer cells and their interplay with tumor associated macrophages

This study investigates two critical aspects of cancer cell metabolism and mitochondrial dynamics: (1) the role of the F1Fo-ATP synthase endogenous hydrolytic inhibitor IF1 in mitochondrial network organization, and (2) the metabolic interaction between neuroblastoma (NBL) cells and tumor-associated macrophages (TAMs), with a focus on the potential role of TLR8 as a microRNA receptor in this interplay. In the first analysis, we explore the function of IF1 in modulating mitochondrial fissionfusion balance, demonstrating that IF1 enhances mitochondrial network interconnection in cancer cells under stress. This may support an elevated oxidative phosphorylation rate in stress condition and may protect IF1-expressing cancer cells from apoptosis. Our findings suggest that IF1 acts as a pro-oncogenic factor, impacting mitochondrial dynamics in addition to its other tumor-promoting activities. Thus, IF1 presents a potential target for cancer therapies, with effects that may vary across different solid tumors. The second focus examines metabolic reprogramming in NBL cells co-cultured with THP-1 monocytes. Preliminary data indicate that TAMs significantly influence NBL cell metabolism, increasing their metabolic rate, potentially highlighting a pro-tumoral role of TAMs. Notably, the two NBL cell lines tested displayed diverse glucose and lactate utilization patterns, underscoring intratumorally metabolic heterogeneity. TLR8 expression in monocytes appears pivotal for this reprogramming, possibly altering the tumor microenvironment (TME) by influencing nutrient availability. Metabolic shifts in both NBL cells and TAMs suggest bidirectional reprogramming, likely proceeding in opposing metabolic directions. Future studies are needed to elucidate the precise mechanisms driving this metabolic reprogramming, potentially mediated by extracellular vesicles (EVs) and miRNAs, with TLR8 emerging as a key component in this process. This work emphasizes the value of co-culture models in cancer bioenergetics research, as they partially recapitulate the complex interactions between tumor and immune cells that are instrumental in cancer progression and metabolic adaptation.