3. Mitophagy and inflammation
Mitophagy effectively alleviates inflammation, while defective mitophagy usually elicits inflammatory responses in mammalian cells. InAtg5 (autophagy related 5)-deficient C57BL/6 J mice administered with angiotensin II, impaired mitophagy results in enhanced ROS production, and, subsequently, NFKB1 (nuclear factor kappa B subunit 1) activation, causing inflammation and cardiac damage (Vincent et al., 2020). Therefore, mitophagy anomaly culminates in inflammation, suggesting a role for mitophagy in alleviation of inflammation. Also, impaired mitophagy can lead to sterile inflammation as mutation in DNM1L results in mitophagy defect, mitochondrial depolarization, loss of ATP, and myocardial inflammation in a murine model of dilated cardiomyopathy (Cahill et al., 2015).
It is noteworthy that Mir103 (microRNA 103) inhibits mitophagy through suppressing TRAF3 (TNF receptor associated factor 3; a target molecule of Mir103 ), thus reinforcing inflammation in bothin vitro and in vivo models of adipose inflammation (Zhang, Zhang, Feng, Huang, Xia & Sun, 2019). In addition, ARF3 (ADP ribosylation factor 3) inhibits Mir103 , resulting in TRAF3 upregulation, mitophagy activation, NFKB inhibition, and NLRP3 (NLR family pyrin domain containing 3) inflammasome suppression (Zhang, Zhang, Feng, Huang, Xia & Sun, 2019). Thus, the ARF3-Mir103 -TRAF3 signaling cascade depicts a new paradigm in the regulation of mitophagy and its link with inflammation suppression upon obesity disorders.
Moreover, FUNDC1-mediated mitophagy inhibits activation of the NLRP3 inflammasome, resulting in inhibition of inflammation secondary to intracerebral hemorrhage in murine models (Zheng, Jian, Gan, Wang, Zhao & Zhai, 2021). This study suggests that FUNDC1 is a potential target for inhibition of inflammation. Apart from this, the AJUBA (ajuba LIM protein) molecule participates in PINK1-mediated mitophagy through translocation to depolarized mitochondria (Ponia et al., 2021). In this respect, AJUBA deficiency causes mitophagy impairment and contributes to systemic inflammation upon viral infection in mice (Ponia et al., 2021). Therefore, AJUBA acts as an essential molecule to maintain PINK1-mediated mitophagy and prevent inflammation.
In contrast, some pieces of evidence also suggests that excessive mitophagy can further exacerbate inflammation. For instance, KMT2B (lysine methyltransferase 2B) deficiency culminates in excessive mitophagy, inflammation, and lipolysis in murine white adipose tissues (He et al., 2020). Scrutiny for a role of mitophagy in mitochondrial DNA release demonstrated that PINK1-PRKN-mediated mitophagy evokes mitochondrial DNA release, which in part triggers TLR9 activation (Jing et al., 2020). Subsequently, TLR9 activates MYD88 (MYD88 innate immune signal transduction adaptor)-NFKB1 axis, leading to inflammation inin vivo models of lung injury (Jing et al., 2020). This study suggests that hyperactive mitophagy evokes inflammation through the TLR9-MYD88-NFKB1 pathway. In summary, mild induction of mitophagy is an anti-inflammatory process, indicating that mild induction of mitophagy in macrophages might cease inflammation in atherosclerotic lesions.