How Cells Share Mitochondria Through Nanotubes and Why Miro1 Is the Key Driver

Mitochondrial dysfunction underlies many age-related and degenerative conditions, including neurodegeneration, cardiovascular disease, cancer and chronic inflammation. Cells can sometimes rescue each other by passing mitochondria across direct connections, which has fueled interest in mitochondrial transplantation as a therapy. This review by Zamberlan and Semenzato asks how tunneling nanotubes (TNTs), one of the main contact-dependent routes, actually move mitochondria between cells.

This is a narrative review, not a new experiment. It first places TNTs among other transfer routes: free mitochondria, extracellular vesicles, gap-junction/adhesion-mediated transfer and dendritic structures. It then describes how TNTs form, through actin-driven protrusion (involving M-Sec, RalA, the exocyst, Cdc42, Rac1 and an Eps8–IRSp53 module), cell displacement, or tip-to-tip filopodial bridges. Thin TNTs (about 20–700 nm) contain only actin, while thick TNTs (over 700 nm) also contain microtubules and carry large cargo such as mitochondria over long distances using motor proteins.

The central theme is Miro1, a calcium-sensitive outer mitochondrial membrane protein that couples mitochondria to kinesin and dynein via TRAK/Milton adaptors. In the studies reviewed, Miro1 overexpression in mesenchymal stem cells improved mitochondrial delivery and outcomes in models of stroke, cardiac ischemia, acute lung injury, chemotherapy-induced neurotoxicity, intervertebral disc degeneration, diabetic nephropathy and wound healing. Knockdown or loss of Miro1 reduced transfer and protection. In bone, loss of Miro1 impaired donation from osteolineage to myeloid cells and promoted osteoclast activity in a glucocorticoid-osteoporosis context. In cancer, stromal cells used Miro1-dependent TNTs to restore respiration in mtDNA-deficient tumor cells, and loss of Miro1 delayed tumor formation. A 2024 structural study resolved the MIRO1–TRAK1 complex, showing two non-redundant binding sites that anchor motors to mitochondria independent of calcium.

The review also argues that mitochondrial shape affects transfer. Drp1-mediated fission appears to precede entry into TNTs, and fission/fusion proteins (Mfn1/2, OPA1, Drp1 adaptors) are tuned by post-translational modifications, calcium and ROS. The abstract further points to GFAP, MICAL2PV, CD38, Connexin 43, thymosin β4 and Talin 2 as regulators, and highlights regenerative medicine and oncology as translational areas.

The implication is that Miro1 could be raised to boost tissue repair or blocked to disrupt tumor–stroma mitochondrial exchange. Several caveats apply. The authors note that the molecular determinants of TNT formation are unclear, as are the quality and fate of transferred mitochondria and the best source for isolating mitochondria. The evidence discussed is mostly preclinical (cell culture and rodent models), and the text provided for this summary ends partway through the section on mitochondrial dynamics. The later sections, covering the other regulators and the translational discussion, are therefore described here only from the abstract.