Intercellular Mitochondrial Transfer as a Rescue Mechanism in Response to Protein Import Failure

Abstract

Mitochondrial biogenesis requires the import of most of their proteins from the cytosol. Therefore, efficient import apparatus is vital for eukaryotic cell function, particularly in highly energy demanding cells such as neurons and myocytes. Consequently, dysfunctional mitochondrial protein import is implicated in many diseases. This study explores the molecular basis and consequences of import failure in mammalian cells. We show that blocking import machinery has profound effects on mitochondrial ultra-structure and dynamics, but surprisingly little impact on import. The explanation is a remarkable mechanism in which healthy cells transfer mitochondria to cells with deficient mitochondrial import, and vice versa, through connecting tunnelling nanotubes. These observations suggest the existence of a widespread mechanism for rescue of mitochondrial import function in complex multicellular organisms.

Perturbation of the mitochondrial import machinery by aggregation prone Tau affects organelle morphology and reduces neuronal complexity

“…This is consistent with previous reports that showed Tau P301L accumulation in the OMM and IMS (Cieri et al, 2018; Hu et al, 2016), and suggests that it may be associated with the translocation channel in a similar way to an artificially trapped precursor protein (Chacinska et al, 2003; Ford et al, 2022; Hope I Needs et al, 2022). Surprisingly, however, despite association of Tau P301L with the import machinery, in-cell NanoLuc import assays (Hope I. Needs et al, 2022) showed that the import kinetics of a precursor reporter were not significantly affected (Fig.…”

“…This can be achieved with the small molecule inhibitor MB20 (Cheung, 2017), or with a precursor fused to DHFR which, when bound to methotrexate, becomes trapped in the channel (Chacinska et al, 2003; Ford et al, 2022). While these treatments inhibit import in isolated mitochondria (Cheung, 2017; Ford et al, 2022), we unexpectedly found that they fail to do so within whole cells (Hope I Needs et al, 2022). We wondered if the apparent lack of effect on the whole mitochondrial population of the cell could be explained by a mitochondrial replacement system.…”

“…We wondered if the apparent lack of effect on the whole mitochondrial population of the cell could be explained by a mitochondrial replacement system. We found that, at the whole cell level, defective mitochondrial function is rescued by the recruitment of healthy mitochondria from surrounding cells, and disposal of compromised mitochondria, by way of TNTs (Hope I Needs et al, 2022). Therefore, we were curious if the association of the Tau variant with the import apparatus induced a similar response.…”

“…In a parallel study, we explored the effects of artificially blocking the import machinery (Hope I Needs et al, 2022). This can be achieved with the small molecule inhibitor MB20 (Cheung, 2017), or with a precursor fused to DHFR which, when bound to methotrexate, becomes trapped in the channel (Chacinska et al, 2003; Ford et al, 2022).…”

“…TNTs induced by import impairment contain actin as well as microtubules, which are necessary for mitochondrial movement (Hope I Needs et al, 2022). Thus, drugs that target actin (cytochalasin D) and tubulin (nocodazole) polymerisation inhibit TNT formation (Bittins & Wang, 2017; Kumar et al, 2017; Luchetti et al, 2012).…”