Lineage‐Mismatched Mitochondrial Replacement in an Inducible Mitochondrial Depletion Model Effectively Restores the Original Proteomic Landscape of Recipient Cells

Abstract

AbstractIn addition to critical roles in bioenergetics, mitochondria are key contributors to the regulation of many other functions in cells, ranging from steroidogenesis to apoptosis. Numerous studies further demonstrate that cell type‐specific differences exist in mitochondria, with cells of a given lineage tailoring their endogenous mitochondrial population to suit specific functional needs. These findings, coupled with studies of the therapeutic potential of mitochondrial transplantation, provide a strong impetus to better understand how mitochondria can influence cell function or fate. Here an inducible mitochondrial depletion modelis used to study how cells lacking endogenous mitochondria respond, on a global protein expression level, to transplantation with lineage‐mismatched (LM) mitochondria. It is shown that LM mitochondrial transplantation does not alter the proteomic profile in nonmitochondria–depleted recipient cells; however, enforced depletion of endogenous mitochondria results in dramatic changes in the proteomic landscape, which returns to the predepletion state following internalization of LM mitochondria. These data, derived from a cell system that can be rendered free of influence by endogenous mitochondria, indicate that transplantation of mitochondria—even from a source that differs significantly from the recipient cell population, effectively restores a normal proteomic landscape to cells lacking their own mitochondria.