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Review
. 2023 Jan 1;13(2):736-766.
doi: 10.7150/thno.79876. eCollection 2023.

Cellular mitophagy: Mechanism, roles in diseases and small molecule pharmacological regulation

Yingying Lu  1 , Zhijia Li  1 , Shuangqian Zhang  1 , Tongtong Zhang  2   3 , Yanjun Liu  2   3 , Lan Zhang  1
Affiliations
Review

Cellular mitophagy: Mechanism, roles in diseases and small molecule pharmacological regulation

Yingying Lu et al. Theranostics. .

Abstract

Cellular mitophagy means that cells selectively wrap and degrade damaged mitochondria through an autophagy mechanism, thus maintaining mitochondria and intracellular homeostasis. In recent years, mitophagy has received increasing attention as a research hotspot related to the pathogenesis of clinical diseases, such as neurodegenerative diseases, cardiovascular diseases, cancer, metabolic diseases, and so on. It has been found that the regulation of mitophagy may become a new direction for the treatment of some diseases. In addition, numerous small molecule modulators of mitophagy have also been reported, which provides new opportunities to comprehend the procedure and potential of therapeutic development. Taken together, in this review, we summarize current understanding of the mechanism of mitophagy, discuss the roles of mitophagy and its relationship with diseases, introduce the existing small-molecule pharmacological modulators of mitophagy and further highlight the significance of their development.

Keywords: Diseases; Mechanism; Mitophagy; Small molecule modulators.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
The timeline of some research progress related to mitophagy.
Figure 2
Figure 2
The main processes of mitophagy. When mitochondria are damaged after external stimulation, the damaged mitochondria will depolarize, and the outer membrane potential of the mitochondria will be lost. Subsequently, the autophagosome wraps the mitochondria to become a mitochondrial autophagosome. Lysosomes combine with mitochondrial autophagosomes, thus promoting the degradation of mitochondrial content.
Figure 3
Figure 3
Overview of the mitophagy mechanisms. Mitophagy takes place through many different but interrelated mechanisms, which can usually be divided into Ub-dependent pathways and Ub-independent pathways. Among the Ub-dependent pathways, the PINK1/Parkin pathway is the most common. Besides, a series of mitochondrial autophagic receptors that can directly bind to LC3 without causing extensive ubiquitination are involved in the Ub-independent pathway.
Figure 4
Figure 4
Physiological functions of mitophagy in human diseases. When mitophagy happens normally, it will produce a series of benefits to human body. On the contrary, the accumulation of damaged mitochondria caused by the inactivity of mitophagy will trigger some corresponding diseases.
Figure 5
Figure 5
PINK1-Parkin activity modulators. (A) Kinetin enhanced the activity of PINK1. (B) The p53 inhibitor pifithrin-α promoted the accumulation of Parkin in the mitochondrial outer membrane.
Figure 6
Figure 6
The mechanisms of different mitophagy inducers (A and B) Parkinson's toxins (C) Iron chelators and SIRT1 activators (D) Protonophores.
Figure 7
Figure 7
Mitophagy inducers targeting Nrf2. (A) Sulforaphane (indirectly) and PMI (directly) prevent Nrf2 from being degraded by Keap1, causing the nuclear accumulation of Nf2 which benefit mitochondria. (B) Nrf2 is engaged in controlling mitochondrial activity and gene transcription that activates autophagy. One such gene is p62/SQSTM1, which appears to be crucial for PMI-induced activation of mitophagy.
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