Mitochondrial dynamics and tumor drug resistance. (IMAGE)
Caption
In mitochondrial fusion, MFN1/2 participates in OMM fusion, and then OPA1 mediates IMM fusion and finally completes the mitochondrial fusion process. In mitochondrial fission, ER first marks the fission site, and then DRP1 assembles and mediates mitochondrial fission here.
Mitochondria fusion and fission can, respectively, maintain mitochondrial cristae structure and increase ROS, eventually leading to increased drug resistance in tumors. In the nucleus, PGC-1 interacts with Nrf1/2, resulting in mtDNA transcription, replication, and translation, and vemurafenib, ERR/antagonist, etc., can inhibit this process. Mitophagy is mainly mediated through two pathways: the Ub-dependent pathway and the Ub-independent pathway. The former's proteins on mitochondrial membrane are ubiquitinated by PINK1/Parkin and delivered to autophagosome membrane through connexins NDP52/OPTN/p62/TAX1BP1, while the latter's mitochondrial membrane is directly bound to LC3 by NIX/FUNDC1/BNIP3. Mitochondria are wrapped by an autophagosome, and then fused with a lysosome to finally complete mitophagyOroxylin A, HCQ, Lys05, PIK-III, Gossypol, Phenoformin, etc., can inhibit this process. Mito-associated ER membranes refer to specialized regions where the membranes of the ER and mitochondria are closely apposed or in direct contact. IP3R on ER membrane and VDACs on mitochondrial membrane form IP3R-GRP75-VDACs complex via GRP75 connection, which can mediate the transfer of Ca2+ from ER to mitochondria. This is promoted by cisplatin and inhibited by Bcl-2.
The transfer of Ca2+ can produce calcium overload in the mitochondria and lead to apoptosis through CytC release or ROS production. OMM, outer mitochondrial membrane; MFN, mitofusin; IMM, inner mitochondrial membrane; OPA1, optic atrophy 1; ER, endoplasmic reticulum; DRP1, dynamin-related protein 1; ROS, reactive oxygen species; PGC-1, peroxisome proliferator-activated receptor-γ coactivator-1; Nrf1/2, nuclear respiratory factor 1/2; LC3, light chain 3 protein; NDP52, nuclear dot protein 52; OPTN, optineurin; p62, sequestosome-1; TAX1BP1, Tax1-binding protein 1; Ub, ubiquitin; PINK1, PTEN induced putative kinase 1; NIX, NIP3-like protein X; FUNDC1, FUN14 domain-containing 1; BNIP3, BCL2-interacting protein 3; IP3R, inositol 1,4, 5-trisphosphatereceptor; GRP75, glucose-regulated protein 75; VDAC, voltage-dependent anion channel; Bcl-2, B-cell lymphoma-2; CytC, cytochrome C.
Credit
Chen Huang, Zichuan Xie, Jiajin Li, Chenliang Zhang
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