According to “Global Cancer Statistics- 2022”, colorectal cancer (CRC) ranks third in incidence and second in cancer-related mortality. Given that approximately 50% of cases progress to metastasis and have an unfavorable prognostic rate, CRC represents a significant health and economic burden.

Cellular organelles not only play critical roles in physiological functions but also in the initiation and progression of cancer. Mitochondrial dysfunction is associated with the initiation of various diseases, including developmental disorders, neuromuscular conditions, metabolic disorders, and cancer. Similarly, dysfunction of the endoplasmic reticulum (ER) can lead to ER stress and activation of the unfolded protein response (UPR), which is implicated in diseases such as diabetes, neurodegenerative disorders, cardiovascular ailments, stroke, tumor growth, and chemoresistance.

Inter-communication between mitochondria and the ER, through various signaling pathways, regulates cellular homeostasis and function in both normal cells and tumor cells, primarily through mitochondria-associated endoplasmic reticulum membranes (MAMs). In a recent review published in the Genes & Diseases journal, researchers at Chongqing University and Chongqing University Cancer Hospital review the latest research progress concerning the crosstalk between these organelles in CRC, providing novel insights into the field.

The review provides a brief overview of mitochondria, ER, and MAMs, with a discussion on the role of MAMs in tumorigenesis. MAMs influence tumor progression by regulating Ca2+ homeostasis, lipid metabolism, mitochondrial morphology, and ER stress. The presence of these signaling pathway proteins within the MAMs contributes to epithelial-to-mesenchymal transition, invasion, and resistance to apoptosis across multiple cancers.

Certain oncogenes and tumor suppressors interact with the resident MAM proteins, resulting in Ca2+ homeostasis dysfunction by modulating the flow of Ca2+ from the ER to the mitochondria, thus influencing the fate of cancer cells. Previous research has revealed that altered expression levels of various Ca2+ signaling proteins on MAMs in CRC, including SERCA, IP3R, VDAC, and MCU, cause perturbations in Ca2+ homeostasis, thus influencing the fate of cancer cells. Compounds such as resveratrol (and its derivative paclitaxel), dihydroartemisinin, α-hederin, erastin, and sulindac sulfone have been shown to exert potential anti-CRC activity by regulating Ca2+ homeostasis.

The MAMs also regulate lipid metabolism; altered expression of proteins such as ANKRD22, TRIAP1, and ACSL4 results in changes in lipid composition within the ER and mitochondria of tumor cells, affecting mitochondrial bioenergetics, thus influencing tumor cell survival and its response to chemotherapy.
Additionally, the interplay between mitochondrial fission/fusion, autophagy, and MAMs highlights the pivotal role of MAMs in determining cell fate. Enhancing mitochondrial fusion and inhibiting mitochondrial fission and mitophagy may suppress CRC drug resistance and effectively prolong the survival of CRC patients. Aloe gel glucomannan, tanshinone IIA, cirsiliol, and δ-valerobetaine exert an anti-CRC effect by inhibiting mitophagy.

A close interplay between the components of the MAMs and the UPR has been previously evidenced in CRC. ATAD3A and PGC-1α mitigate ER stress and promote 5-fluorouracil-resistance in CRC cells. Natural compounds, such as thrihydroxyurs-12-en-28-oic acid (TEOA), oleander leaf phenol extract (PEOL), jolkinolide B, and allyl isothiocyanate (AITC), mitigate CRC by triggering ER stress-induced apoptosis.

In conclusion, this review provides an extensive summary of how the cross-talk between mitochondria and ER promotes CRC, while highlighting the critical role of MAMs. Furthermore, the review also provides deep insights into the recent anti-CRC therapeutic strategies targeting the MAMs.

Reference
Title of the original paper: The role of mitochondria-endoplasmic reticulum crosstalk in colorectal cancer

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101766

Funding Information:

• Chongqing Natural Science Foundation (China) (No. CSTB2023NSCQ-MSX0845, CSTB2024NSCQ-MSX0591)
• Shapingba District 2024 Science and Health Joint Medical Research Project, Chongqing, China (No. 2024SQKWLHMS009)
• Open Research Fund Program of the NHC Key Laboratory of Personalized Diagnosis and Treatment for Nasopharyngeal Carcinoma (China) (No. 2023NPCCJ01)
• Open Research Fund Program of the Key Laboratory of Molecular Biology for Infectious Diseases of Chongqing Medical University, China (No. 202406).

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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