Wide Range of Disease
New findings explaining the complicated process by which the "energy substations" of human cells split apart and recombine may lay the groundwork for new treatment approaches to a wide range of diseases, including some cancers and neurodegenerative diseases such as Parkinson's and Alzheimer's.
Researchers from The Johns Hopkins University's Integrated Imaging Center; the University of California, Davis; and the California Institute of Technology collaborated on two new studies analyzing the mechanisms and proteins that underlie the fission-fusion cycle of the cellular powerplants, called mitochondria. Their findings were published in two recent issues of the journal Science. "To understand the role that mitochondria play in both normal and aberrant cell biology, it is essential to first understand the fusion-fission process that occurs continuously in normal, healthy cells," said J. Michael McCaffery, a research scientist in the Johns Hopkins Department of Biology, director of the Integrated Imaging Center, and an author on both studies.
Mitochondria constantly split and recombine and as cells divide, they pass along to each "daughter" cell the full complement of mitochondria necessary for healthy cell physiology. Recent research suggests that when this process goes awry, healthy cells die, resulting in diseases ranging from optic atrophy (the most common inherited form of blindness), to Charcot-Marie-Tooth disease (a disease in which nerves in the hands, feet and lower legs die off), to Parkinson's and Alzheimer's diseases (which arise from neurodegenerative cell death), and even to some types of cancer.
Until now, though, understanding of those diseases was greatly limited by a lack of knowledge about the mitochondrial fusion portion of the cycle.
"Fusion of single membranes is a well-delineated process, involving well-known, well-studied proteins," McCaffery said. "However, the same cannot be said for mitochondrial fusion, in which the key sequence of events and facilitating proteins remain largely unknown."
The mitochondrial fusion process is challenging to understand because mitochondria are structurally very complex, double-membrane bound organelles. In order for separate mitochondria to fuse, two distinct, compositionally very different membranes must join. Understanding how mitochondria accomplish this while maintaining the integrity of their compartments and the appropriate segregation of membranes and proteins is a fundamental question that the researchers sought to answer.
McCaffery's team helped tackle this question by studying isolated mitochondria that had been removed from cells, observing them in test tubes using both light and electron microscopy. This cell-free approach allowed researchers a first-ever glimpse into the sequence of events underlying outer and inner membrane fusion.
What they discovered — that mitochondria removed from their host-cell environment were nonetheless able to fuse — surprised them because it suggested that mitochondria contain within themselves all the proteins necessary for fusion. This stands in stark contrast to the process of single-membrane fusion, which requires many additional cellular proteins to carry out this important function.
"We observed two distinct stages, with the first involving outer membrane fusion yielding an intermediate structure of two conjoined mitochondria, followed by the subsequent fusion of the inner membranes giving rise to a single mitochondrion," McCaffery said. "Understanding the discrete molecular events that underlie dynamic mitochondrial behavior has the potential to reveal keen insights into the basic and essential cell-mitochondria relationship, leading to increased understanding of the aging process; and potential treatments and perhaps cures of those age-related scourges of Parkinson's and Alzheimer's."
The research was supported by the National Institutes of Health. The findings were reported in the Science editions of Aug. 6 and Sept. 17. ("Structural Basis of Mitochondrial Tetheting by Mitofusion Complexes," 305:858-862; "Mitochondria Fusion Intermediates Revealed in Vitro," 305:1747-1752.)
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