Targeting mitochondrial autophagy for anti-aging

Abstract

Mitochondrial dysfunction is one of the core drivers of aging. It is manifested by reactive oxygen species (ROS) accumulation, mitochondrial DNA (mtDNA) mutations, imbalanced energy metabolism, and abnormal biosynthesis. Mitochondrial autophagy maintains cellular homeostasis by selectively removing damaged mitochondria through mechanisms including the ubiquitin-dependent pathway (PINK1/Parkin pathway) and the ubiquitin-independent pathway (mediated by receptors such as BNIP3/FUNDC1). During aging, the decrease in mitochondrial autophagy efficiency leads to the accumulation of damaged mitochondria, forming a cycle of mitochondrial damage-ROS-aging damage and aggravating aging-related diseases such as neurodegenerative diseases and cardiovascular pathologies. The targeted regulation of mitochondrial autophagy (drug modulation and exercise intervention) can restore mitochondrial function and slow aging. However, autophagy has a double-edged sword effect; moderate activation is anti-aging, but excessive activation or dysfunction accelerates the pathological process. Therefore, targeting mitochondrial autophagy may be an effective anti-aging technique; however, future focus should be on the tissue-specific regulatory threshold and the dynamic balance mechanism to achieve precise intervention.

Fig. 1

Drivers and features of aging.

Fig. 2. Mitochondrial autophagy process and mechanism.

Mitochondrial autophagy proceeds through four stages: membrane potential dissipation of mitochondria-mitochondrial autophagosome formation-autophagosome fusion with lysosome-mitochondrial contents are degraded by lysosomes. a PINK1-Parkin‐mediated mitophagy. When mitochondria are damaged, the input of PINK1 is hindered and accumulates on the outer mitochondrial membrane. PINK1 then phosphorylates Ub, which then binds to RING1, resulting in the release of RING2 and the exposure of the E2 interaction surface in RING1. RING2 then receives ubiquitin from E2 and transfers it to the substrate. Parkin is activated to ubiquitinate mitochondrial substrates on OMM, allowing LC3 attached to autophagosomes to be recruited through autophagy adaptors OPTN and NDP52, among others. b PINK-Parkin-independent mitophagy. FUNDC1, NIX, BNIP3, BCL2L13, and FKBP8 can bind LC3 alone to mediate mitochondrial autophagy. During reticulocyte maturation, the autophagic receptors NIX, FUNDC1, and BNIP3 are strongly activated, resulting in increased receptor levels on the OMM. Among them, BNIP3 can induce mitochondrial rupture and promote the separation of damaged mitochondria by promoting Drp1. At the same time, BNIP3 recruits Parkin to mitochondria and activates mitochondrial autophagy. Furthermore, hypoxia enhances PGAM5-mediated FUNDC1 dephosphorylation, while FUNDC1 dephosphorylation and mitochondrial fission mediated by FUNDC1-Drp1 complex binding jointly promote mitochondrial autophagy.

Fig. 3

Dual roles of autophagy: protective barrier and pathology driver.

Fig. 4

Gene regulation.

Fig. 5. Mitochondrial quality control.

a Healthy mitochondria. The damaged parts of mitochondria split from the healthy parts by split proteins and are encapsulated by autophagosomes for mitochondrial autophagy. While the healthy part of the mitochondria fuses with other mitochondria to achieve its anti-aging function. b Damaged mitochondria. Protein misfolding, mtROS and mtDNA leakage, and oxidative phosphorylation damage can all activate URPmt. URPmt initiation induces ATF4 to bind to CHOP, while ATF5 directly acts on the mitochondrial chaperone promoter, upregulating the expression of HSPA9 and LONP1 to rebuild homeostasis in mitochondria. In addition, PERK further activates the expression of ATF4 by phosphorylating eIF2α, thereby repairing oxidative phosphorylation damage. c Mitochondrial dysfunction. Aging causes decreased expression of PGC-1α and AMPK and impaired ETC, which in turn affects the normal transcription of autophagy genes, upregulates mTOR expression, and leaks ROS and mtDNA, ultimately exacerbating mitochondrial dysfunction.

Fig. 6

Protein homeostasis network.

Fig. 7

Links between aging and inflammation.

Fig. 8

Comparison of TALEN with CRISPR-Cas9.