Double-Edged Sword: Exploring the Mitochondria-Complement Bidirectional Connection in Cellular Response and Disease

Overview

Journal Biology (Basel)

Publisher MDPI

Specialty Biology

Date 2024 Jun 27

PMID 38927311

Authors

Jingfei Carly Lin

Sinwoo Wendy Hwang

Honglin Luo

Yasir Mohamud

Affiliations

Soon will be listed here.

Abstract

Mitochondria serve an ultimate purpose that seeks to balance the life and death of cells, a role that extends well beyond the tissue and organ systems to impact not only normal physiology but also the pathogenesis of diverse diseases. Theorized to have originated from ancient proto-bacteria, mitochondria share similarities with bacterial cells, including their own circular DNA, double-membrane structures, and fission dynamics. It is no surprise, then, that mitochondria interact with a bacterium-targeting immune pathway known as a complement system. The complement system is an ancient and sophisticated arm of the immune response that serves as the body's first line of defense against microbial invaders. It operates through a complex cascade of protein activations, rapidly identifying and neutralizing pathogens, and even aiding in the clearance of damaged cells and immune complexes. This dynamic system, intertwining innate and adaptive immunity, holds secrets to understanding numerous diseases. In this review, we explore the bidirectional interplay between mitochondrial dysfunction and the complement system through the release of mitochondrial damage-associated molecular patterns. Additionally, we explore several mitochondria- and complement-related diseases and the potential for new therapeutic strategies.

Citing Articles

Mitochondrial injury and complement dysregulation are drivers of pathological inflammation in viral myocarditis.

Mohamud Y, Bahreyni A, Hwang S, Lin J, Wang Z, Zhang J J Virol. 2025; 99(2):e0180424.

PMID: 39846741 PMC: 11852726. DOI: 10.1128/jvi.01804-24.

References

Salari N, Morddarvanjoghi F, Abdolmaleki A, Rasoulpoor S, Khaleghi A, Afshar Hezarkhani L . The global prevalence of myocardial infarction: a systematic review and meta-analysis. BMC Cardiovasc Disord. 2023; 23(1):206. PMC: 10122825. DOI: 10.1186/s12872-023-03231-w. View

Yevgi R, Demir R . Oxidative stress activity of fingolimod in multiple sclerosis. Clin Neurol Neurosurg. 2021; 202:106500. DOI: 10.1016/j.clineuro.2021.106500. View

Oleesky D, Daniels R, Williams B, Amos N, Morgan B . Terminal complement complexes and C1/C1 inhibitor complexes in rheumatoid arthritis and other arthritic conditions. Clin Exp Immunol. 1991; 84(2):250-5. PMC: 1535395. View

Ozen A, Kasap N, Vujkovic-Cvijin I, Apps R, Cheung F, Karakoc-Aydiner E . Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease. Nat Immunol. 2021; 22(2):128-139. PMC: 7856263. DOI: 10.1038/s41590-020-00830-z. View

Thurman J, Renner B, Kunchithapautham K, Ferreira V, Pangburn M, Ablonczy Z . Oxidative stress renders retinal pigment epithelial cells susceptible to complement-mediated injury. J Biol Chem. 2009; 284(25):16939-16947. PMC: 2719331. DOI: 10.1074/jbc.M808166200. View

Yanagawa B, Spiller O, Proctor D, Choy J, Luo H, Zhang H . Soluble recombinant coxsackievirus and adenovirus receptor abrogates coxsackievirus b3-mediated pancreatitis and myocarditis in mice. J Infect Dis. 2004; 189(8):1431-9. DOI: 10.1086/382598. View

Villalpando-Rodriguez G, Gibson S . Reactive Oxygen Species (ROS) Regulates Different Types of Cell Death by Acting as a Rheostat. Oxid Med Cell Longev. 2021; 2021:9912436. PMC: 8380163. DOI: 10.1155/2021/9912436. View

Odendall C, Kagan J . Activation and pathogenic manipulation of the sensors of the innate immune system. Microbes Infect. 2017; 19(4-5):229-237. PMC: 6697111. DOI: 10.1016/j.micinf.2017.01.003. View

Collard C, Agah A, Stahl G . Complement activation following reoxygenation of hypoxic human endothelial cells: role of intracellular reactive oxygen species, NF-kappaB and new protein synthesis. Immunopharmacology. 1998; 39(1):39-50. DOI: 10.1016/s0162-3109(97)00096-9. View

10.

Guo C, Sun L, Chen X, Zhang D . Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res. 2014; 8(21):2003-14. PMC: 4145906. DOI: 10.3969/j.issn.1673-5374.2013.21.009. View

11.

Moraes-Silva I, Rodrigues B, Coelho-Junior H, Feriani D, Irigoyen M . Myocardial Infarction and Exercise Training: Evidence from Basic Science. Adv Exp Med Biol. 2017; 999:139-153. DOI: 10.1007/978-981-10-4307-9_9. View

12.

Ratajczak M, Mack A, Bujko K, Domingues A, Pedziwiatr D, Kucia M . ATP-Nlrp3 Inflammasome-Complement Cascade Axis in Sterile Brain Inflammation in Psychiatric Patients and its Impact on Stem Cell Trafficking. Stem Cell Rev Rep. 2019; 15(4):497-505. PMC: 6647482. DOI: 10.1007/s12015-019-09888-1. View

13.

Lintner K, Wu Y, Yang Y, Spencer C, Hauptmann G, Hebert L . Early Components of the Complement Classical Activation Pathway in Human Systemic Autoimmune Diseases. Front Immunol. 2016; 7:36. PMC: 4753731. DOI: 10.3389/fimmu.2016.00036. View

14.

Luan X, Lei T, Fang J, Liu X, Fu H, Li Y . Blockade of C5a receptor unleashes tumor-associated macrophage antitumor response and enhances CXCL9-dependent CD8 T cell activity. Mol Ther. 2023; 32(2):469-489. PMC: 10861991. DOI: 10.1016/j.ymthe.2023.12.010. View

15.

Wang L, Wang F, Gershwin M . Human autoimmune diseases: a comprehensive update. J Intern Med. 2015; 278(4):369-95. DOI: 10.1111/joim.12395. View

16.

Galvan M, Greenlee-Wacker M, Bohlson S . C1q and phagocytosis: the perfect complement to a good meal. J Leukoc Biol. 2012; 92(3):489-97. DOI: 10.1189/jlb.0212099. View

17.

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

18.

Strainic M, Liu J, Huang D, An F, Lalli P, Muqim N . Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells. Immunity. 2008; 28(3):425-35. PMC: 2646383. DOI: 10.1016/j.immuni.2008.02.001. View

19.

Rozenberg P, Ziporen L, Gancz D, Saar-Ray M, Fishelson Z . Cooperation between Hsp90 and mortalin/GRP75 in resistance to cell death induced by complement C5b-9. Cell Death Dis. 2018; 9(2):150. PMC: 5833442. DOI: 10.1038/s41419-017-0240-z. View

20.

Yang J, Ahn H, Chang M, Narasimhan P, Chan P, Song Y . Complement component 3 inhibition by an antioxidant is neuroprotective after cerebral ischemia and reperfusion in mice. J Neurochem. 2012; 124(4):523-35. PMC: 3557607. DOI: 10.1111/jnc.12111. View