After delivery: How recipient cells shape the fate and function of transplanted mitochondria

Abstract

Background

Mitochondrial transplantation is built on a simple idea: failing cells might be rescued by healthy mitochondria. The approach has entered early clinical testing, and encapsulation and cell-type targeting have improved uptake in selected systems. Better delivery, however, does not explain the therapy.

Main body

Internalised donor mitochondria encounter an established network, quality-control machinery and sensors for mitochondrial material. Donor material may remain in the endolysosomal system or reach the cytosol. Cytosolic fates include network integration, clearance and a candidate functional contribution without fusion. Intracellular processing may also generate bioactive cargo. These fates imply different mechanisms and evidence requirements. This Review examines how recipient cells shape the contribution of internalised mitochondria, while recognising extracellular routes to benefit. We distinguish direct transplantation evidence from mechanistic support drawn from endogenous mitochondrial biology and natural intercellular transfer. The required donor fate and duration depend on the therapeutic task. Transient rescue may rely on short-term donor function or productive processing in specific models; sustained support may depend on continued donor function, recipient adaptation or redosing. Durable mitochondrial DNA (mtDNA) correction requires donor-mtDNA retention and replication.

Conclusions

Linking these tasks to product design, safety assessment and clinical endpoints shifts the question from how many mitochondria enter cells to what they accomplish after arrival.

Key points

• Recipient-cell handling shapes what transplanted mitochondria do after uptake.
• Uptake, structural integration and donor mitochondrial DNA retention require distinct evidence.
• Transient rescue, sustained support and durable mitochondrial DNA correction impose different requirements.
• Therapeutic goals should guide donor selection, product testing and clinical endpoints.