Determination of Altered Mitochondria Ultrastructure by Electron Microscopy - Protein Misfolding and Cellular Stress in Disease and Aging - page 267

and a sausage-like morphology. The overall size and shape of
mitochondria depend on their location within the cell. In the
cytoplasm of neurons, they are generally sausage-shaped, about
0.1 mm wide and 1.0 mm long ( 1 ). In axons, the mitochondria
tend to assume a highly elongated form, while they are more
globoid in the synaptic terminals. Mitochondria are highly motile
and are constantly moving in a directed manner along cytoskeletal
tracks within cells. They are surrounded by an outer, smooth
membrane and an inner, folded membrane forming the cristae
which fill the interior of the organelle. The inner mitochondrial
membrane encloses a space referred to as the matrix. The space
between the inner and outer membranes is referred to as the
intermembrane space. The outer membrane contains many voltage-
dependent anion channels (also called mitochondrial porins).
These channels are approximately 3 nm in diameter and are perme-
able to uncharged molecules up to 5,000 Da ( 2 ). Thus, although
small molecules, ions, and metabolites can enter the intermem-
brane space, they cannot penetrate the inner membrane. Therefore,
the environment of the intermembrane space is similar to that
of the cytoplasm with respect to ions and small molecules. The
inner membrane that forms the cristae contains proteins, the major
functions of which include: (1) performing the oxidation reac-
tions of the respiratory electron-transport chain, (2) synthesizing
ATP, and (3) regulating transport of metabolites into and out of
the matrix ( 2 ). The enzymes of the respiratory chain are attached
to the inner membrane and project their heads into the matrix.
The intermembrane space contains specific enzymes such as
creatine kinase, adenylate kinase, and cytochrome c. The matrix
contains the soluble enzymes of the citric acid cycle (Krebs cycle)
and the enzymes involved in fatty acid beta-oxidation. When one
mitochondrion merges with another one, not only the membranes
of the two mitochondria but also their contents merge, including
the matrix compartment that contains the mitochondrial DNA.
Conversely, by a fission event, a single mitochondrion becomes
two mitochondria. Because of these complementary processes, the
identity of any individual mitochondrion is transient.
Mitochondria play a complex role in the pathogenesis of
neurodegenerative diseases due to their involvement in a number
of processes, including the regulation of excitotoxicity, the
homeostasis of intracellular Ca 2+ , the production of reactive oxy-
gen species, and apoptotic processes. Although respiratory chain
defects have been reported in patients with neurodegenerative
diseases, clear pathogenic mutations in mtDNA or respiratory
chain-related nuclear genes have been rarely observed ( 3, 4 ).
On the other hand, numerous mutations in genes encoding mito-
chondrial proteins not related to or indirectly related to the
respiratory chain have been identified ( 5 ) in the various different