Mitochondria Findings May Help Beat Wide Range Of Disease

From: An Metet (anmetet_at_freedom.gmsociety.org)
Date: 10/16/04 

Date: Sat, 16 Oct 2004 09:09:05 -0400

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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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