The power and potential of mitochondria transfer

Abstract

Mitochondria are believed to have originated through an ancient endosymbiotic process in which proteobacteria were captured and co-opted for energy production and cellular metabolism. Mitochondria segregate during cell division and differentiation, with vertical inheritance of mitochondria and the mitochondrial DNA genome from parent to daughter cells. However, an emerging body of literature indicates that some cell types export their mitochondria for delivery to developmentally unrelated cell types, a process called intercellular mitochondria transfer. In this Review, we describe the mechanisms by which mitochondria are transferred between cells and discuss how intercellular mitochondria transfer regulates the physiology and function of various organ systems in health and disease. In particular, we discuss the role of mitochondria transfer in regulating cellular metabolism, cancer, the immune system, maintenance of tissue homeostasis, mitochondrial quality control, wound healing and adipose tissue function. We also highlight the potential of targeting intercellular mitochondria transfer as a therapeutic strategy to treat human diseases and augment cellular therapies.

Figure 1.. Mechanisms of mitochondria transfer.

Cells transfer mitochondria through transient cellular connections, such as tunneling nanotubes, that depend on Connexin (Cx) 43, Growth associated protein 43 (GAP43), and Mitochondrial Rho GTPase 1 (Miro1) shuttle. In addition, mitochondria are exported from cells via multivesicular bodies. Mitochondria-derived vesicles and whole mitochondria are packaged in CD9-, CD63-, and/or CD81-studded vesicles or LC3-studded exophers, which are released as extracellular vesicles (EVs) in a Rab7-GDP-dependent manner for capture by recipient cells. Mitochondria are also released in EVs via budding off the plasma membrane. The recipient cell degrades mitochondria captured in EVs via the lysosome. Finally, free mitochondria are released from cells and then captured by recipient cells in a heparan sulfate (HS)-dependent manner. Captured mitochondria can then be degraded via the lysosome, with some evidence suggesting they might escape into the cytoplasm.

Figure 2.. Functional roles of mitochondria transfer.

Mitochondria are transferred between cells in tissue- and cell-type-specific mechanisms and have been linked to various physiologic and pathologic processes in diverse tissues. a | In the central nervous system astrocytes deliver mitochondria to neurons to support their survival in ischemic stroke, whereas in the peripheral nervous system macrophages deliver mitochondria to neurons in the dorsal root ganglia to limit inflammatory pain signal propagation. b | Cancer cells obtain mitochondria from immune cells such a T cells and macrophages, impairing anti-tumor immunity while also supporting the cellular metabolic demands of cancer cells and driving their proliferation. c | Adipocytes and cardiomyocytes transfer damaged mitochondria to macrophages for elimination and preservation of mitochondria quality of the donor cell. d | In wounded skin, activated platelets seal the damaged vessel and deliver their mitochondria to mesenchymal stem cells (MSCs) to promote angiogenesis and wound healing as well as to neutrophils to promote antimicrobial defense. e | Mitochondria transfer enhances hematopoietic stem cell (HSC) engraftment and contributes to eliciting hematopoiesis. f | MSCs also transfer mitochondria to T cells to promote regulatory T cell differentiation and inhibit pro-inflammatory cytokine production, limiting joint damage in arthritis. g | In white adipose tissue, adipocytes transfer mitochondria to macrophages to support maintenance of tissue homeostasis, a process that is impaired in obesity to divert adipocyte mitochondria into the blood for interorgan transport to the heart, where cell-free mitochondria elicit an antioxidant response that protects the heart from ischemia-reperfusion injury. h | In the bone, osteoblasts transfer mitochondria to their progenitors to reinforce osteoblast differentiation and promote bone formation, and osteocytes transfer mitochondria along dendritic networks to support their metabolism and bone mineral homeostasis.