Mitochondria research (mentions CMT)

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Mitochondria Findings May Help Beat Wide Range of Disease

http://www.jhu.edu/~news_info/news/home04/oct04/mitochon.html

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 s Hopkins University's Integrated Imaging

Center; the University of California, ; 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. McCaffery, a

research scientist in the s 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.)