Hematopoietic stem cell conditioned media induces excessive mitochondrial fission via Drp-1 to target colorectal cancer

Abstract

Mitochondria, often referred to as the "powerhouses of the cell," are particularly crucial in cancer cells due to their high energy demands. Mitochondrial fusion-fission dynamics play a critical role in regulating signaling pathways and metabolic activities in colorectal cancer (CRC) cells. Increased mitochondrial fission drives metabolic reprogramming, enabling CRCs to proliferate, metastasize, and resist chemotherapy. Paradoxically, excessive fission induces mitochondria-mediated apoptosis. Our previous studies have shown that hematopoietic stem cell-derived conditioned media (CM) modulate the apoptosis pathway and mitochondrial bioenergetics of cancer stem cells by altering the cancer microenvironment. In this study, We found that HSCs-CM facilitates excessive fission in colorectal cancer cells by modulating Drp-1 and concurrently activating the PINK1-Parkin mitophagy pathway and intrinsic apoptosis, leading to loss of viability of these cells. Moreover, proteomics data showed that HSCs-CM dysregulated the electron transport chain complexes, with an exceptionally high degree of dysregulation of complexes III and IV. Metabolomics revealed dysregulation of critical metabolites, RNA sequencing revealed dysregulation of transcripts, and proteomics revealed dysregulation of proteins, involved in mitochondrial bioenergetics and the autophagy pathway in CRCs treated with CM. Taken together, our studies reveal the therapeutic potential of HSC-conditioned media for treating colorectal cancer. HighlightsO_LIHematopoietic stem cell-derived conditioned media (HSC-CM) induces excessive mitochondrial fission in colorectal cancer (CRC) cells by upregulating Drp-1, thereby activating the intrinsic apoptotic pathway. C_LIO_LIExcessive fission and bioenergetic dysfunction caused by HSC-CM result in loss of mitochondrial membrane potential and elevated reactive oxygen species production. C_LIO_LIHSC-CM severely disrupts the electron transport chain in CRC cells, precipitating an energy crisis and engaging the PINK1-mediated mitophagy pathway. C_LI SummaryHematopoietic stem cell-derived conditioned media (HSC-CM) compromises mitochondrial dynamics by inducing excessive fission in colorectal cancer (CRC) cells through upregulation of Drp-1 and its associated protein complex. The resulting hyperfission leads to severe mitochondrial dysfunction, characterised by a loss of mitochondrial membrane potential, decreased ATP production, and disrupted electron transport chain complexes. This bioenergetic crisis and overproduction of reactive oxygen species ultimately trigger intrinsic apoptosis and engage the mitophagy pathway, leading to loss of CRC cell viability.