Transmitophagy in the heart: An overview of molecular mechanisms and implications for pathophysiology

Figures

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  Figure 1. Mitophagy in cardiomyocytes—Parkin-dependent and Parkin-independent mechanisms. Mitophagy in cardiomyocytes involves both Parkin-dependent and Parkin-independent pathways for clearing damaged mitochondria. In the Parkin-dependent pathway, PINK1 accumulates on depolarized mitochondria, recruiting Parkin, which ubiquitinates mitochondrial proteins. These proteins are recognized by autophagy receptors (e.g., p62, NDP52, OPTN), which then bind to LC3 on the autophagosome for degradation in lysosomes. In the Parkin-independent pathway, damaged mitochondria are cleared via Mitochondrial-Derived Vesicles (MDVs) and receptor-mediated mitophagy. BNIP3, Nix (BNIP3L), and FUNDC1 recruit LC3, facilitating autophagic degradation. Additionally, cardiolipin externalization marks damaged mitochondria for clearance by directly interacting with LC3. Furthermore, mitochondrial fission through Drp1 action enables Rab9-mediated mitophagy. MDVs bud off from mitochondria and can translocate and fuse with lysosomes to execute mitophagy.

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  Figure 2. Intercellular mitochondrial transfer—pathways and molecular players. Mitochondria or fragments are transferred between cells by several mechanisms. Exophers (1–5 μm) encapsulate damaged mitochondria and other debris, which are extruded from cardiomyocytes and engulfed by macrophages through recognition of phosphatidylserine (PS) by the MerTK receptor. Migrasomes (∼3 μm), formed during cell migration, carry mitochondria and contain markers like TSPAN4 and NDST1, facilitating uptake by macrophages. Tunneling nanotubes (TNTs) (50–200 nm), up to 200 μm long, are actin-based conduits that connect cells, allowing direct mitochondrial transfer from cardiomyocytes to fibroblasts, macrophages, and neighboring cardiomyocytes, regulated by Myo10 (Myosin-X) and the Exocyst complex. Extracellular vesicles (EVs) (30–1000 nm) shuttle mitochondrial fragments to macrophages and fibroblasts. Tight and gap junctions facilitate the transfer of small molecules like ATP through specialized channels, with gap junctions allowing direct transfer of molecules through ∼1–2 nm channels. Figure generated in BioRender.

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  Figure 3. Exophers and transmitophagy. In C. elegans neurons, oxidative stress or proteasomal inhibition triggers the formation of exophers that encapsulate damaged mitochondria and protein aggregates, which are ejected and cleared by glial cells. This process involves intermediate filaments and autophagy adaptor p62 (SQST-1), with HDAC6 and FTT-2 modulating exopher production, and CED-1, CED-6 and CED-7 modulating exopher clearance. Fasting also induces exophers through pathways involving lipid synthesis, FGF/RAS/MAPK and EGF/RAS/MAPK signaling. In mammalian cardiomyocytes, mitochondrial dysfunction leads to exopher formation with mitochondria exhibiting decreased Opa1, Fis1 and Cytc. Exophers exhibit PS exposure on the membrane for recognition by MerTK receptors on macrophages. Figure generated in BioRender.

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  Figure 4. Migrasome formation and mitocytosis in mammalian cells. Migrasomes consist of NDST1, PIGK, CPQ, and EOGT. They form during cell migration or stress in migrating cells. Damaged mitochondria can be disposed of through migrasomes in a process also called mitocytosis, which has been shown to be associated with low-intensity pulsed ultrasound-induced cardioprotection in a TSPAN-4 dependent manner66. Figure generated in BioRender.

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  Figure 5. Tunneling nanotube (TNT)-mediated mitochondrial transfer. Dysfunctional mitochondria are transferred from cardiomyocytes to neighboring cells (macrophages, fibroblasts, and neighboring cardiomyocytes) via TNTs. TNT formation is driven by actin polymerization, with Myo10 and the Exocyst complex stabilizing the nanotube structure. Rab GTPases (Rab8a and Rab11) help regulate TNT formation. PS on apoptotic membrane can serve as a signal that promotes TNT-mediated interactions with recipient cells. Figure generated in BioRender.

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  Figure 6. Transmitophagy in development, aging, and diseases in the heart. This schematic describes cell-autonomous mitophagy and transmitophagy in the developing, adult and aging heart. (A) There is evidence that during development, TNTs mediate exchange of extracellular vesicles and cargo between neighboring cells, and resident cardiac macrophages around cardiomyocytes support mitochondrial homeostasis. (B) In adult heart, cell-autonomous mitophagy and transmitophagy both can occur; the latter may be mediated by TNTs and exophers. (C) In aging heart, cell–autonomous mitophagy and lysosomal capacity are reduced. Whether there is elevation of transmitophagy pathways including those through TNT and exophers need further investigation. (D) β-Adrenergic stress, ischemia/reperfusion, and oxidative stress affect transmitophagy, through MerTK-dependent macrophage uptake, TSPAN4-mediated migrasomes/mitocytosis, and TNTs. Figure generated in BioRender.

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  Figure 7. Therapeutic implications of transmitophagy. Graphical summary of potential therapeutic interventions targeting transmitophagy via exophers, migrasomes, and tunneling nanotubes (TNTs). Exopher pathway: damaged mitochondria are packaged into large vesicular exophers and cleared by MerTK-expressing macrophages. Potential therapeutic modulation includes MerTK activation of transmitophagy, complemented by healthy mitochondrial transplantation and mitochondria-targeted antioxidants (SkQ1, MitoQ) to improve mitochondrial quality. Another strategy is to increase macrophages that can scavenge damaged mitochondria from cardiomyocytes. Migrasome pathway: mitochondrial fragments are extruded along retraction fibers into TSPAN4-positive migrasomes, where they undergo mitocytosis and are degraded by neighboring cells. Potential targeting includes TSPAN4 activators to increase migrasome biogenesis, and complemented by low-intensity pulsed ultrasound (LIPUS) to increase mitocytosis. TNT pathway: F-actin–based TNTs, regulated by Myo10, Miro1, and actin polymerization dynamics, mediate direct transfer of mitochondria between cardiomyocytes and/or recipient macrophages or fibroblasts. Potential…