Engineering Cardiomyocyte Function by Controlled Mitochondrial Transfer
Abstract
Topic Area(s) Addressed: This project aligns with Fiscal Year 2020 Peer Reviewed Medical Research Program Topic Areas Mitochondrial Disease and Congenital Heart Disease and is of considerable significance to US military Service members and Veterans. Every cell in the human body, except red blood cells, contains mitochondria, which are small biological factories that produce energy and small molecules called metabolites by breaking down ingested nutrients, such as sugars and fats. Mitochondria are required for life and participate in processes that sustain health for individual cells and whole organisms. Recent studies revealed a surprising feature previously unknown about mitochondria, which is that they can migrate into cells from the surrounding tissue environment, or even from cell to cell, in order to maintain the status quo and provide support in situations that stress cells. This migration, which remains poorly understood, is important to recovering cell and tissue function in response to damage. Specifically, after a heart attack due to clogged arteries, transfer of mitochondria may be essential in the repair of the damaged heart muscle. Transfer of mitochondria may also be an understudied phenomenon in patients with weakened hearts, known as heart failure. This proposal will investigate the fate of mitochondria placed into new host cells and also examine the changes induced by this acquisition on heart cell functions in order to manipulate this process and facilitate heart repair for a variety of stresses and diseases. To study how internalized mitochondria induce repair to injured heart cells, a device was invented called “MitoPunch” that can efficiently transfer mitochondria into a large number of cells simultaneously, recreating in a controlled setting mitochondrial acquisition that can occur for cells within the body. MitoPunch will be used to deliver precise amounts of mitochondria into human skin cells, which can then be converted into heart cells, also called cardiomyocytes, by a widely adopted and now standard laboratory technique called cellular reprogramming. This approach is necessary because commonly used heart muscle cells acquired from the body have limited lifespans and diversity when grown in a dish outside the body. Performing mitochondrial transfer to make “designer” heart muscle cells for long-term studies avoids this lifespan roadblock. MitoPunch will also be used to transfer mitochondria into these designer heart cells to determine whether the mitochondria temporarily or more permanently boost the metabolism of the new host heart cells. Studies here will also examine whether the transferred mitochondria remain in the new host heart cells permanently, to remodel the native mitochondrial population and change heart cell function, such as beat frequency and rhythm. Other studies have shown that acquired mitochondria helps to repair cardiac injury, whereas here advanced techniques will be used to evaluate the genetic and physical changes that occur in heart cells that acquired mitochondria by transfer from the environment using MitoPunch. Understanding the heart cell response for integration, cooperation, or rejection of non-native mitochondria provides new opportunities in cell-environment communications in response to and repair of heart cell damage. This knowledge is crucial to the potential development of medicines that can stimulate mitochondrial transfer and integration in new host heart cells, to one day improve damaged heart cell functions and treat cardiomyopathies and heart attacks. Additionally, our proposed study will provide fresh insight to ameliorate mitochondrial disease, which affects thousands of active duty Service personnel and Veterans, through mitochondrial transfer. This will in turn help push forward the development of therapies directed at alleviating disabilities, such as heart diseases, in these individuals.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110139
Entities
People
- Michael A Teitell
Organizations
- United States Army
- University of California, Los Angeles