Figure 11.

A novel working model shows the function, classification, and regulated mechanisms of OCRGs in diseases, and DAMP- and virus-treated cells. (A) The membrane contact sites between two organelles, at least between ER and mitochondria (Mito, MT), have been found to play several significant functions from previous reports and our study, such as in metabolism (including gluconeogenesis, glycogen synthesis and breakdown, fat storage, hormone metabolism, drug metabolism, lipid biosynthesis, and homeostasis), Ca²⁺ transport, organelle communication ROS, apoptosis, autophagy/mitophagy, and DAMP communication. (B) Thirteen of 16 functional groups of OCRGs are differently modulated in various diseases and cancers. Three groups of OCRGs such as vesicle, mitochondrial fission, and mitophagy were identified as the cell crisis-handling OCRGs (red line pointed). Seven groups of OCRGs including three cell crisis-handling OCRGs plus sarcoplasmic reticulum-mito, mitochondrial fusion, autophagosome–lysosome fusion, and autophagosome/endosome–lysosome fusion were identified as the cell failure-handling OCRGs (blue line pointed). Autophagosome–lysosome fusion OCRGs can be regarded as virus infection-suppressed OCRGs (brown line pointed). Eight classification groups (i.e., vesicle, MT fission, mitophagy, sarcoplasmic reticulum–MT, autophagosome–lysosome fusion, ER–MT contact, ER–PM junctions, and ER–endosome) are Treg plastic OCRGs (purple line pointed). Ten groups of ECs activation by DAMP OCRGs include seven Treg plastic OCRGs (except autophagosome–lysosome fusion) and add MT fusion, autophagosome/endosome–lysosome fusion, and ER–GC interaction OCRGs (green line pointed). Vesicle regulators can be regarded as oncogenes and tumor suppressor-promoted OCRGs (light blue line pointed). (C) Extracellular pathogen-associated molecular patterns (PAMPs)/damage-associated molecular patterns (DAMPs), cytokines, and viruses act via their receptors including TLRs on the cell membrane and intracellular locations (Nod-like receptors and inflammasomes) to activate OCRGs directly or indirectly by activating intracellular organelle dangers first and then OCRGs. And ROS regulator NRF2 oncogenes and tumor suppressors also regulate the expression of OCRGs in diseases and tumors. A new concept that the organelle crosstalk serves as both new DAMP sensing and communicating network and new cell crisis and cell failure-handling network to fulfill both physiological functions and pathological functions. *Created with BioRender.com.