Mitochondrial dysfunction induces radioresistance in colorectal cancer by activating [Ca2+]m-PDP1-PDH-histone acetylation retrograde signaling

Abstract

Mitochondrial retrograde signaling (mito-RTG) triggered by mitochondrial dysfunction plays a potential role in regulating tumor metabolic reprogramming and cellular sensitivity to radiation. Our previous studies showed phos-pyruvate dehydrogenase (p-PDH) and PDK1, which involved in aerobic glycolysis, were positively correlated with radioresistance, but how they initiate and work in the mito-RTG pathway is still unknown. Our further genomics analysis revealed that complex I components were widely downregulated in mitochondrial dysfunction model. In the present study, high expression of p-PDH was found in the complex I deficient cells and induced radioresistance. Mechanistically, complex I defects led to a decreased PDH both in cytoplasm and nucleus through [Ca2+]m-PDP1-PDH axis, and decreased PDH in nucleus promote DNA damage repair (DDR) response via reducing histone acetylation. Meanwhile, NDUFS1 (an important component of the complex I) overexpression could enhance the complex I activity, reverse glycolysis and resensitize cancer cells to radiation in vivo and in vitro. Furthermore, low NDUFS1 and PDH expression were validated to be correlated with poor tumor regression grading (TRG) in local advanced colorectal cancer (CRC) patients underwent neoadjuvant radiotherapy. Here, we propose that the [Ca2+]m-PDP1-PDH-histone acetylation retrograde signaling activated by mitochondrial complex I defects contribute to cancer cell radioresistance, which provides new insight in the understanding of the mito-RTG. For the first time, we reveal that NDUFS1 could be served as a promising predictor of radiosensitivity and modification of complex I function may improve clinical benefits of radiotherapy in CRC.

An integrated bioinformatic investigation of mitochondrial energy metabolism genes in colon adenocarcinoma followed by preliminary validation of CPT2 in tumor immune infiltration

“…Shi et al. found that mitochondrial dysfunction can enhance the resistance of COAD to radiotherapy, thus promoting tumor progression ( 25 ). Cheng et al.…”

Overcoming Radiation Resistance in Gliomas by Targeting Metabolism and DNA Repair Pathways

“…PDH complex plays an important role in citric acid cycle and aerobic glycolysis. A recent study suggested that reduced PDH activity can promote cancer cells to repair DNA damages through mitochondrial retrograde signaling [56]. It has recently been found that PKM2 is highly expressed in cancer cells and reshapes cancer metabolic programming.…”

Biological Mechanisms to Reduce Radioresistance and Increase the Efficacy of Radiotherapy: State of the Art

“…A transient decrease in mitochondrial function has been observed in cancer cell lines shortly after exposure to IR, which correlates with the oxidizing effects of IR [ 132 ] and could be considered for tumor radioresistance. Indeed, colon and lung cancer cells that shift their metabolism to glycolysis because of mitochondria depletion manifest radioresistance [ 133 , 134 ]. On the other hand, an increase in mitochondrial abundance and a high oxidative metabolism have been reported in radioresistant vs. radiosensitive human HNSCC cells [ 135 ].…”