Recommendations for mitochondria transfer and transplantation research

BIRMINGHAM, Ala. – Most animal, plant and fungal cells contain organelles called mitochondria. These descendants of a primordial bacterial endosymbiont still preserve distinct genes and are known for their ability to create ATP as chemical energy. They also have other important functions, including cell signaling, viral and bacterial sensing, cell division, cell death, and innate and adaptive immune responses. Consequently, impairment in mitochondrial function can result in aging and age-related diseases.

An emerging area of research is the evolutionarily conserved transfer of mitochondria between cells. Yet researchers have lacked unique and universally accepted terms and practices to describe such transfers. Absent an agreed nomenclature and standard practices, different researchers may use different methods and terminology to describe the same event, or they may employ the same term that actually describe two different processes.

“Over the past few years, we have come to understand that mitochondria can be transferred from one cell to another, and that isolated mitochondria can be transplanted like an organ transplant,” said Keshav K. Singh, Ph.D., professor in the University of Alabama at Birmingham Department of Genetics. “Though the origins of mitochondria transfer are unclear, it has been observed in evolutionarily diverse eukaryotes, including yeast, mollusks, fish and rodents, as well as human cells. We are just beginning to understand how alterations in this process contribute to disease pathogenesis and how to harness mitochondria transfer and transplantation biology to develop new therapies.”

In 2024, Singh and Jonathan Brestoff, M.D., Ph.D., Washington University School of Medicine, Saint Louis, Missouri, set up an international consortium on mitochondria transfer and transplantation and led an international team of 31 researchers to develop consensus and recommendations about how to advance the field by providing common terminology and characterizations for the transfer or transplantation of mitochondria. Their consensus paper, “Recommendations for mitochondria transfer and transplantation nomenclature and characterization,” is published in the journal Nature Metabolism.

The paper begins with a brief history of the field — some foundational early discoveries, recent studies of mitochondrial transfer and development of therapeutic approaches, including cell engineering and clinical trials for children requiring extracorporeal membrane oxygenation.

The paper defines types of mitochondria transfer and mitochondria transplantation, and when both the donor and acceptor cell types are established in vivo, that defines a mitochondria transfer axis. The paper reviews methods to define mitochondria transfer, including mitochondria reporter proteins and dyes, methods to enforce transfer, and discussion of the fate of mitochondria after cell entry. Mechanism-based nomenclature is roughly grouped into contact-dependent mitochondria transfer, where the donor cell and recipient cell touch each other, and contact-independent mitochondria transfer.

The recommendations also review therapeutic approaches of mitochondria transplantation, including the definition of transplants; the types, durability, degree of engraftment and heterogeneity of transplants; cell engineering using extracellular mitochondria; and drugs that affect mitochondria transfer. Extracellular mitochondria are common in humans — for example there are about 3 billion to 12 billion extracellular mitochondria in a unit of blood platelets, a blood product that is routinely and safely transfused to patients intravenously.

The paper concludes that “the goal of this proposed nomenclature is to reduce the confusion that can be caused by the introduction of different names for similar processes or extracellular mitochondria subsets as this field has evolved. We recognize that mitochondria transfer and transplantation are very active areas of research and that it is possible that new findings and insights may necessitate updates to the proposed nomenclature.”

Singh has a long-standing interest in mitochondria. He was founding editor-in-chief of the journal Mitochondrion and the founder of the Society for Mitochondria Research and Medicine. In 2007 and 2009, his laboratory showed that isolated mouse mitochondria can be transferred to human cells by co-incubation, providing a proof of principle for transfer of mitochondria by diffusion, and that xeno-transplanted platelet mitochondria from an African American woman who suffered aggressive breast cancer at young age was able to recapitulate aggressiveness of breast cancer in mice. At that time, these findings were not appreciated by the field, Singh says.

Along with corresponding authors Singh and Bresthoff, 29 other researchers are co-authors of the Nature Metabolism paper.

At UAB, Genetics is a department in the Marnix E. Heersink School of Medicine.