Recent advances and applications of mitochondria in tumors and inflammation

Abstract

Mitochondria are bilayer membrane organelles with basic metabolic activity. They are considered hubs for biosynthesis, bioenergy, and signaling functions, coordinating major biological pathways. Mitochondria are coupled to the oxidation of fatty acids and pyruvate through electron transport chains and have historically been considered the primary source of cellular energy. Recent studies have depicted that mitochondria are centers that promote inflammatory responses and play a crucial role in combating pathogenic infections. Moreover, mitochondria provide the basis for tumor synthesis metabolism, control redox and calcium homeostasis, participate in transcriptional regulation, and control cell death. Mitochondria are involved in all steps of tumorigenesis. This review discusses the relationship between mitochondria (including mitochondrial metabolism and mitophagy) and tumors, and the relationship between mtDNA and inflammation, as well as its clinical application in inflammatory diseases. More importantly, the application and targeted treatment strategies provide more opportunities for the development of new anticancer drugs.

Keywords: Inflammation; Metabolism; Mitochondria; Tumor.

Fig. 1

(A) Mitochondria are a key link in inflammation regulation;(B) Mitochondria can regulate cellular signal transduction processes；(C) Mitochondria are still the main site of ROS (reactive oxygen species) or free radicals generation, and are crucial for resisting infections. However, excessive ROS generation may lead to cell and tissue damage; (D) Mitochondrial DNA (mtDNA) is released into the cytoplasm and extracellular environment, activating various pattern recognition receptors and innate immune responses, including the cGAS STING pathway, TLR9 receptors, and inflammasome formation, thereby triggering a strong type I interferon response.

Fig. 2

Acute and chronic inflammatory diseases and aging processes are associated with the accumulation of ROS and RNS, which may be due to respiratory chain dysfunction caused by mitochondrial genome instability. Cytoplasmic chromatin fragments (CCF) extruded from the senescent nucleus trigger SASP by activating the innate immune cell sololytic DNA receptor cGAS-STING pathway. Aging cells inhibit NK and CD8 + T cell clearance by upregulating HLA-E, promoting APC mediated chronic inflammation. They can also enhance T cell activation through APCs (such as dendritic cells), leading to chronic inflammation and tissue damage. Notably, the accumulation of mitochondrial DNA (mtDNA) mutations impairs mitochondrial respiration, leading to the accumulation of mitochondrial reactive oxygen species (mtROS). This accelerates the emergence of new mtDNA mutations, leading to a vicious cycle and cellular aging

Fig. 3

Flowchart 1: Regulatory pathways of mitochondrial autophagy