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
Researchers from Johns Hopkins' Integrated Imaging
Center, the University of California at 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 power plants,
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," says J. Michael
McCaffery, a research scientist in the Johns Hopkins
Biology, director of the
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
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 says. "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
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 the finding 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 says. "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
The research was supported by the National Institutes
of Health. The findings were reported in the Science
editions of Aug. 6 and Sept. 17.