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.