Traffic 2001 2: 235–244
Munksgaard International Publishers
Copyright C Munksgaard 2001
ISSN 1398–9219
Review
The Many Shapes of Mitochondrial Membranes
Lorena Griparic and
Alexander M. van der Bliek*
Department of Biological Chemistry, University of California,
Los Angeles CA 90095, USA
*Corresponding author: Alexander M. van der Bliek,
[email protected]
Attachment of Mitochondria and Motility
Mitochondrial movements were first observed over 80 years
ago, although at the time mitochondria were merely curiosities with no known functions (6). The advent of vital dyes in
the early 1980s and green fluorescent protein (GFP) fusion
proteins in the mid 1990s have made it much easier to follow
The roles of mitochondria in cell death and in aging
have generated much excitement in recent years. At
the same time, however, a quiet revolution in our
thinking about mitochondrial ultrastructure has begun.
This revolution started with the use of vital dyes and
of green fluorescent protein fusion proteins, showing
that mitochondria are very dynamic structures that
constantly move, divide and fuse throughout the life of
a cell. More recently, some of the first proteins contributing to these various processes have been discovered. Our view of the internal structures of mitochondria has also changed. Three-dimensional reconstructions obtained with high voltage electron
microscopy show that cristae are often connected to
the mitochondrial inner membrane by thin tubules.
These new insights are brought to bear on the wealth
of data collected by conventional electron microscopic
analysis.
Key words: drp1, dynamin, fuzzy onions, mgm1, mitochondrial cristae, mitochondrial division, mitochondrial
fusion
Received 19 January 2001, revised and accepted for
publication 23 January 2001
The classic image of mitochondria, as taught in textbooks
for many years, is that of little sausages floating through the
cytoplasm. Cross-sections of mitochondria usually depict
cristae as folds of the mitochondrial inner membrane. However, both of these images are oversimplified. Mitochondria
are now known to be motile and to undergo frequent divisions or to fuse with other mitochondria (1–3). Sometimes
mitochondria exist as a single elaborate network and at other
times they become fragmented (Figure 1). Cristae are also
highly variable. They can take on many different shapes, depending on the cell type and on the patho-physiological state
of the cell (4). Often cristae are simply tubes or they are
flattened chambers with thin tubular connections to the inner
boundary membrane (5). This review attempts to synthesize
these more sophisticated morphological interpretations with
newly discovered molecular mechanisms for fission and fusion.
Figure 1: Typical distribution of mitochondria in a mammalian tissue culture cell. The mitochondria of C2C12 cells
(mouse myoblasts) were observed in vivo by staining with the vital
dye MitoTracker.
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the movement of mitochondria in live cells (1,7,8). We now
know that mitochondria often move rapidly along microtubules, sometimes in a seemingly deliberate fashion. For example, mitochondria are transported along microtubules to
synapses or growth cones in neurons (9). Motor proteins are
likely to play a role in this directional transport. At least two
mitochondrion-specific kinesin heavy chains have been identified in mammalian cells, as have mitochondrion-associated
kinesin light chains (10–12). The association between mitochondria and microtubules also places mitochondria close to
endoplasmic reticulum (ER) membranes. This proximity is no
accident, for there is ample evidence for the exchange of
calcium and other substances between these two organelles
(13). Furthermore, mammalian mitochondria have been seen
associated with intermediate filaments (14). The ability to
control the whereabouts of mitochondria suggests that these
organelles communicate with the surrounding cytoplasm, but
the mechanisms by which this is achieved remain to be discovered.
In contrast with mitochondria from higher eukaryotes, mitochondria from budding yeast are tethered to the actin cytoskeleton (15). Genetic screens for yeast mutants that have
abnormal mitochondrial distributions have led to the discovery of a series of putative mitochondrial attachment proteins. The proteins, called Mmm1p, Mdm10p and Mdm12p,
are all mitochondrial outer membrane proteins, which may
act together as an attachment site for the actin cytoskeleton
(16–19). A cytosolic protein, called mdm20p, is also involved
in attachment of mitochondria to the actin cytoskeleton in
yeast (20). Mitochondria of higher eukaryotes do not have
homologues of the yeast mitochondrial attachment proteins,
because they do not use actin filaments for their distribution.
Another cytosolic factor that affects mitochondrial distribution is called cluA or clu1, a protein first discovered in
Dictyostelium and later also found in yeast, but the function
of this protein has not yet been established (21,22). It will
be of great interest to learn whether the different transport
mechanisms are coupled to sensory mechanisms that signal
the need for mitochondria in specific locations.
Mitochondria may vary greatly in length, but their diameters
are relatively constant in most cells (0.5–1.0 mm) (4). It is conceivable that mitochondrial attachments help maintain the
tubular shape of mitochondria by stretching them out. However, the shape of mitochondria is not affected by disrupting
microtubules with nocodazole (23). Furthermore, mitochondria retain their tubular shape when isolated in isotonic medium (24). It would thus appear that the tubular shape is
largely determined by internal structures of unknown origin.
Division of the Mitochondrial Outer
Membrane
Mitochondria divide during cell division, providing daughter
cells with a normal complement of mitochondria. Mitochondrial mass increases from the onset of S-phase though M236
phase (25). It is therefore likely that mitochondrial division
and fusion processes are differentially regulated at different
stages of the cell cycle, although this has not yet been
studied in detail. There are, however, instances in which mitochondrial divisions are not tied to the cell cycle. For example,
muscle mitochondria will proliferate during myogenesis, but
also following exercise (26,27). Mitochondrial division can be
induced by a wide range of substances, including benzodiazepine, inhibitors of oxidative phosphorylation, phorbol esters and calcium fluxes (1,28–30). In vertebrates, the numbers of mitochondria are further controlled by thyroid hormones, such as T3, which broadly influence metabolic rates
in vertebrates and may specifically induce mitochondrial division (31). Although there are scattered reports of a mitochondrial T3 receptor, the mechanisms by which these hormones
exert their control are unknown (31). It is thus fair to say that
the regulatory systems controlling mitochondrial division are
still a black box.
There has been more progress towards understanding the
mechanism of mitochondrial division, since it was first discovered that a dynamin-related protein affects mitochondrial
morphology (32,33). Mutations in this dynamin-related protein, called Dnm1 in yeast, and a homologous protein from
C. elegans, called DRP-1, block mitochondrial division (Figure
2) (34–36). The role of DRP-1 in mitochondrial division was
confirmed by the discovery that the rate of division is increased when wildtype DRP-1 is overexpressed in C. elegans
(36). Further evidence for the role in mitochondrial division
comes from localization studies. Immuno-electron microscopy (34) and immunofluorescence (35,36) show that
Dnm1 and DRP-1 colocalize with constrictions in mitochondria. The spots can coincide with actual division events as
shown by time-lapse photography (36). The appearance of
DRP-1 spots before division and their disappearance after
division suggest that DRP-1 cycles on and off of mitochondria, similar to the cycling of dynamin between the cytosol
and the plasma membrane (36).
Mammalian Drp1 is also localized in spots on mitochondria
that coincide with points of division, and it was shown that
mutations in mammalian Drp1 also inhibit mitochondrial division (23). It is therefore likely that Drp1 is a general factor
controlling mitochondrial division. It was found that purified
Drp1 can assemble in vitro into a ring-like structure with dimensions similar to the dimensions of dynamin spirals (23).
This assembly property suggests that Drp1 can multimerize
into a spiral in vivo. This spiral may wrap around a constricted
part of the mitochondrial outer membrane analogous to dynamin spirals, which wrap around the constricted parts of nascent vesicles at the plasma membrane. Drp1 may therefore
control the final stage in the mitochondrial division process:
severing of the mitochondrial outer membrane.
There are a number of earlier electron microscopy (EM)
studies reporting electron-dense filaments on the surface of
the mitochondria from higher eukaryotes. Frog heart muscles
and some human lymphocytes have regularly spaced filaTraffic 2001; 2: 235–244
Mitochondrial Morphology
each other in vitro, they colocalize in spots on mitochondria
and they have similar mutant phenotypes, indicating that
these two proteins are part of the same mitochondrial division apparatus in yeast (44,45). There are, however, no obvious homologues of Mdv1/Fis2/Gag3 in higher eukaryotes,
suggesting that its function may have been taken over by
a different protein. The other protein affecting mitochondrial
division is an integral protein of the mitochondrial outer membrane called Fis1 or Mdv2 (43,44). Fis1/Mdv2 protein is
evenly distributed along the surface of the mitochondria, unlike Dnm1 and Mdv1/Fis2/Gag3, which are concentrated in
spots. This localization and the mutant phenotype suggest
that Fis1/Mdv2 is required for the assembly of a productive
mitochondrial division apparatus, but is not necessarily incorporated into that apparatus. The precise interplay between
these factors is still under investigation.
Figure 2: Interconnected mitochondria in a C. elegans
muscle cell with mutant DRP-1. Blockage of outer membrane
division by mutant DRP-1 shifts the balance between fission and
fusion towards fusion, leading to an extended network of interconnected mitochondria. Note, however, that inner membrane division
still occurs. Mitochondria were detected in live cells with GFP variants. The mitochondrial outer membrane is shown in green and
the mitochondrial matrix is shown in red. See Labrousse et al. for
experimental details (36).
ments in places where two mitochondria are in close contact
(37,38). These filaments appear to form a junction between
the mitochondria. It is, however, not yet clear whether these
filaments are part of the division apparatus or play some
other role. Electron-dense filaments have also been observed
on mitochondria in other cell types (39–41). Lattices of electron-dense filaments have also been observed on the surfaces of mitochondria, for example in cells with experimental
Parkinson’s and on the surface of sperm mitochondria
(39,42). With the available Drp1 antibodies, it should be
possible to determine whether these filaments are somehow
connected to mitochondrial division.
Recently, several novel factors were discovered that interact
genetically with yeast Dnm1 to help mediate scission of the
mitochondrial outer membrane. The first of the two new
genes encodes a cytosolic protein with a coiled coil domain
and seven WD repeats. This protein was called Mdv1, Fis2
and Gag3 (43–45). Mdv1/Fis2/Gag3 and Dnm1 bind to
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It is not difficult to imagine that the first endosymbiotic bacteria used dynamin of the host cell during entry at the plasma
membrane and used it again during division of its outer
membrane, before eventually giving rise to modern-day mitochondria (46). Other components of the endocytic machinery
might have also been co-opted by the mitochondrial division
apparatus. One possibility was suggested by the recent discovery that a mammalian isoform of synaptojanin, which is
also important for endocytosis, affects mitochondrial morphology (47). Synaptojanin has two inositol-phosphatase domains and appears to affect actin assembly (48). It is not yet
clear whether synaptojanin also contributes to mitochondrial
division. Nevertheless, the striking parallels between endocytosis and division of the mitochondrial outer membranes
suggest a common evolutionary origin. It seems likely that
the mechanism of outer membrane division was derived
from the endocytic mechanism upon entry of the first endosymbiont into the host cell. These common origins may be
further substantiated if more components that are shared between endocytosis and division of the mitochondrial outer
membrane are found.
Division of the Mitochondrial Inner
Membrane
The two mitochondrial membranes almost always divide simultaneously, which raises the possibility that cleavage of the
inner membrane is forced by constriction of the mitochondrial outer membrane. There are, however, a number of welldocumented instances where division of the inner membrane
occurs without concurrent division of the outer membrane,
indicating that a separate inner membrane division apparatus
exists (Figure 3). This type of division is frequently observed
in cells with rapidly dividing mitochondria, such as fat cells
of metamorphosing butterflies (49). The matrix compartment
becomes divided by septae, which are detectable by electron
microscopy, and then later the outer membrane divides. Septation is observed at a low frequency in many mammalian
tissues (50) and at a relatively high frequency in cardiac
muscles (51).
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Figure 3: Partitioning of mitochondria by inner membrane septae. In some normal cells inner membrane division can occur without
outer membrane division, thereby demonstrating that a separable inner membrane division mechanism exists. Panel A shows partitioned
mitochondria in a cardiac muscle cell from a normal mouse. Note that the cristae in the different lobes are differently oriented, emphasizing
that they are completely separate. Panel B shows partitioned mitochondria in the fat body of a butterfly (Calpodes ethlius). Reproduced
from (51) and (49) with permission from Wiley-Liss, Inc., a subsidiary of John Wiley & Sons Inc., and The Journal of Cell Biology 1970; 47:
373–383 by permission of the Rockefeller University Press.
Septation of the mitochondrial inner membrane can also be
induced experimentally. Riboflavin deficiency causes rats to
develop giant mitochondria. When riboflavin is added back
to the diet, these mitochondria first become septated and
then undergo complete division (52). Similar septae have
been observed in mitochondria of cells treated with a variety
of other agents that induce rapid mitochondrial division, such
as dinitrophenol (DNP), A23187, caffeine and chloroform
(30,53,54). Division of the mitochondrial inner membrane
without division of the mitochondrial outer membrane has
also been observed with mutant DRP-1 (36) or with mutant
MGM-1 (M. D. Zappaterra and A. M. van der Bliek, unpublished) in C. elegans muscle cells. It is therefore likely that
animal mitochondria possess a separate mechanism for division of the mitochondrial inner membrane. This mechanism
usually, but not always, acts in concert with division of the
mitochondrial outer membrane.
The endosymbiont origin of mitochondria raises the possibility that proteins acting on the mitochondrial inner membrane are of bacterial descent. Most bacteria divide using a
protein complex built around a ring of FtsZ proteins (55). The
FtsZ ring adheres to the inside of the bacterial membrane by
binding to other proteins such as FtsA, FtsQ and ZipA. This
complex forms a preseptal ingrowth, which mediates division
by further invagination. Chloroplasts also use an FtsZ-like protein for division (56), as do the mitochondria of the algal spe238
cies Mallomonas splendens (57). None of the available animal or yeast sequences contain an obvious homologue of
FtsZ, suggesting that FtsZ was replaced by other proteins in
the course of evolution (58). These novel proteins could be
of bacterial or of eukaryotic descent, but none have been
found yet.
Prior to the discovery of proteins contributing to mitochondrial division, there have been a number of EM observations
of electron-dense rings at constrictions in alga mitochondria,
suggestive of a proteinaceous division apparatus. These electron-dense collars were called mitochondrial division rings
(59). These collars wrap around constrictions of the outer
membrane (60). Sometimes faint electron-dense rings have
been observed in the mitochondrial matrix (61). Similar collars
and rings have been observed in chloroplasts (62). It now
seems likely that the matrix ring is composed of FtsZ (57). It
is, however, less likely that the outer membrane ring contains
FtsZ, because all known examples of FtsZ rings act on the
inner surface of membranes (63). The outer ring might instead contain a dynamin-like protein, acting in tandem with
an inner FtsZ ring. This is an intriguing possibility, because
such a hybrid mechanism is also expected of a primitive
mitochondrial division apparatus.
Factors that couple the division of mitochondrial inner and
outer membranes are not known, nor are factors that couple
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membrane division to other aspects of mitochondrial division.
One protein that is required for the maintenance of mitochondrial DNA has been identified in yeast. This protein, called
Mgm101p, is incorporated into mitochondrial nucleoids
where it binds to mitochondrial DNA (see cover illustration)
(64). It was, however, also found that Mgm101p is required
to repair oxidatively damaged DNA. Loss of mitochondrial
DNA could directly result from faulty DNA repair. Alternatively, mitochondrial DNA could be lost by missegregation, if
that were a secondary consequence of faulty DNA repair. As
with all other aspects of mitochondrial morphology, much
more remains to be learned.
Fusion Between Mitochondria
Mitochondrial fusion and fission events usually compensate
each other, thereby maintaining a relatively constant number
of mitochondria. Mitochondria can become joined into an
elaborate network when mitochondrial fusion becomes
prevalent (23,34–36). Examples of highly connected mitochondria can be found in certain mammalian tissues, such
as skeletal muscles, and in budding yeast (3,65). The latter
often contains only one mitochondrion that is highly branched. The connectivity of mitochondria may help distribute energy, in the form of membrane potential, or ions, as might be
the case with calcium. In higher eukaryotes where fragmented mitochondria are more common, fusion may help
mix mitochondrial DNAs. These DNAs often accumulate
point mutations, thereby rendering mitochondria inactive if
they were to remain isolated from other mitochondria (4,66).
One protein that contributes to mitochondrial fusion was
identified in a Drosophila mutant called fzo, which stands
for fuzzy onions (67). This Drosophila mutant has a normal
phenotype, except during spermatogenesis. At a specific
stage of spermatogenesis the mitochondria would normally
fuse into two large mitochondria that wrap around each other
to form an onion-like structure known as the ‘Nebenkern’.
However, the fzo mutants have mitochondria that can cluster
but fail to fuse. The gene corresponding to fzo encodes a
large GTPase, distantly related to dynamin, but with several
transmembrane domains. The Fzo protein is targeted to mitochondria. The homologous gene from yeast also affects mitochondrial fusion (66). Deletion of the Fzo homologue, called
Fzo1p, shifts the balance between fission and fusion of mitochondria towards fission. The mitochondria become excessively fragmented and are eventually lost, presumably by missegregation of the mitochondrial DNA or of the mitochondria
themselves. The opposite effect, excessive fusion, is induced
when the yeast Drp1 homologue Dnm1p is deleted. In these
cells, the normally branched mitochondria are converted into
a closed net that sits on one side of the cell (34,35). These
results indicate that the branched morphology of wildtype
mitochondria is the result of a delicate balance between fission and fusion processes.
The broad effect of Fzo1p mutations in yeast contrasts with
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the restricted effects in Drosophila, where it would appear
that only spermatogenesis is affected. The Drosophila genomic sequence contains an fzo-like protein, which could conceivably be a more general fusion factor (Accession number
AAF46161). Yeast Fzo1p is part of an 800-kDa complex that
connects the mitochondrial outer and inner membranes (68).
This complex may also contain other proteins that are essential for mitochondrial fusion. A possible second fusion protein
is a recently discovered splice variant of the vesicle-associated membrane protein VAMP-1 (69). VAMP-1 is a SNARE
normally associated with fusion between secretory vesicles
and the plasma membrane (70). The new splice variant,
termed VAMP-1B, has an alternative C-terminus that targets
this protein to mitochondria. The proposed function of
VAMP-1B in mitochondrial fusion has not yet been tested.
Changing Views of Mitochondrial Cristae
Mitochondrial cristae are commonly viewed as infoldings of
the inner membrane, as originally proposed by Palade in the
1950s (71). This lamellar model of cristae was already challenged at its inception by Sjöstrand, who proposed that cristae are disk-shaped chambers that are not connected to the
inner membrane (72). A compromise was struck by Andersson-Cedergren and by Daems and Wisse, who proposed that
cristae are connected to the inner membrane by thin tubules
(73). These models have been difficult to verify by conventional EM. However, in the last 5 years it has been possible
to obtain high-resolution 3D images of mitochondrial cristae
using tomography of thick sections that are viewed with high
voltage EM at different angles. Three-dimensional reconstructions by the laboratories of Mannella and Frey clearly
show chambers of variable shapes that are connected to the
mitochondrial inner boundary membrane by thin tubules
(Figure 4) (74,75). This revised model of cristae is called the
cristae-junction model (5).
Over the years many other types of mitochondrial cristae
have been observed. In some cells, cristae are short tubular
invaginations, protruding inwards from the mitochondrial inner boundary membrane (76). In other cells, these tubules
span the width of the matrix compartment, thus connecting
twice to the inner boundary membrane (76,77). The cristae
of steroid-producing adrenal cells are often flask-shaped
buds on the inside of the inner boundary membrane (Figure
5A) (78). These buds can extend to become tubulo-vesicular
cristae (79) and sometimes they even appear to separate
from the inner boundary membrane, forming vesicles within
the mitochondrial matrix (Figure 5B) (78,80).
How might cristae be formed? It is no longer clear whether lamellar cristae exist, but if they do, then it is easy to imagine that
they are formed as folds in the mitochondrial inner membrane.
The other cristae morphologies described above all require
more elaborate mechanisms. Unfortunately, the rest of this
discussion must remain speculative, because none of the molecules involved in cristae formation are known. The first step is
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Griparic and van der Bliek
Figure 4: Three-dimensional reconstruction of a mitochondrion by electron tomography. The inner membrane is shown in
red. Cristae, which branch off from the inner membrane, are shown in
various colors. The mitochondrion was reconstructed from a frozenhydrated suspension using cryo electron microscopy and computer
assisted tomography (100). Courtesy of Dr. C. A. Mannella.
likely to be the formation of tubular or flask-shaped invaginations from the inner boundary membrane. Coat proteins could
drive the invagination, similar to the role of coat proteins in the
cytosol. Alternatively, invagination could be driven by zippering
up of proteins along the lumen of the cristae. Such a mechanism has been proposed for the formation of tubular invaginations containing photosynthetic proteins in nonsulfur purple
bacteria (Rhodobacter and Rhodospheroides) (81). These
bacteria belong to the group of a-proteobacteria from which
mitochondria are derived. The dimensions of their tubules are
similar to those of mitochondrial cristae, suggesting that they
may be distantly related to cristae.
A second step in cristae formation is likely to be the placement
of a physical constraint on the diameter of the tubular connections with the inner boundary membrane. These junctions are
relatively small (28 nm in diameter) (5). They are also small in
adrenal cells which may have flask-shaped cristae with narrow
openings (78). Treatments that induce different energetic
states can enlarge or reduce the space within cristae without
noticeably changing the diameters of cristae junctions (74).
The cristae junctions may form a barrier, controlling the entry
and release of solutes to and from cristae. Cristae junctions
could therefore help set up concentration gradients of ions, or
help to sequester cytochrome c. Cristae junctions could also
serve to retain membrane proteins within cristae, since it was
shown by DAB staining of mitochondria that oxidative activity
is concentrated in the lumen of cristae (82).
Surprisingly, the EM data indicate that cristae membranes are
often capable of fusion, while in rare cases fission might also
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Figure 5: Flask-shaped and vesicular cristae in adrenal cortex cells. Panel A shows a cell in the transition between the zona
glomerulosa and the zona fasciculata of the adrenal cortex of a rat.
This rat was treated with corticotropin-releasing hormone, which
stimulates steroid production. Note the flask-shaped cristae connected to the inner boundary membrane of the mitochondria. Panel
B shows a cell in the zona fasciculata with mitochondria containing
many vesicular cristae. Reprinted by permission of Wiley-Liss, Inc.,
a subsidiary of John Wiley & Sons Inc. (78).
occur. Fusion is indicated by the existence of more than one
connection between individual cristae and the inner membrane (5,83). The cristae observed with EM tomography often
have several connections to the inner membrane, while tubular
cristae are also often connected on both sides to the mitochondrial inner membrane (74,75). Fusion between cristae, or between cristae and the inner membrane, must therefore be
quite common. The occurrence of fission within mitochondria
is not as clear. It may occur only in a few specialized cell types,
since cristae almost always appear to be connected to the inner membrane. One exception could be mitochondria from
steroid-producing adrenal cortex cells, which appear to contain physically separated vesicles in images obtained with conTraffic 2001; 2: 235–244
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ventional EM. This separation has not yet been confirmed by
EM tomography (78). There is, however, also a human myopathy in which the separation of vesicles from the inner boundary membrane has been confirmed by EM tomography (5). It
would therefore appear that the mitochondrial matrix contains
its own membrane fission and fusion mechanisms. Perhaps
mitochondria contain a relic of a primitive vesicular transport
pathway. This would be all the more remarkable considering
that mitochondria also contain distinct mechanisms for the
fission and fusion of the inner and outer membranes, as discussed in previous sections. Discovery of the molecular mechanisms underlying each of these various processes will no
doubt help clarify their origins.
Morphological Aberrations Induced by
Pathological Conditions
Mitochondria are adversely affected by a wide variety of
pathological conditions, including toxicity, nutrient deficiency
and heritable diseases (4). Heritable diseases may directly
affect mitochondrial morphology, if they are caused by mutations in mitochondrial DNA or in nuclear genes encoding
mitochondrial proteins. Other diseases may indirectly affect
mitochondrial morphology, such as Alzheimer’s and Parkinson’s diseases, which have primary defects elsewhere in
the cell that are so disruptive that mitochondria are affected
too. There are several recent reviews of the role of mitochondria in various disease states (84–86), and a thorough exposition of ultrastructural abnormalities has been given by
Ghadially (87). Here, we will briefly discuss the most common aberrations and then focus on possible connections to
morphological factors.
ease therefore depend on the copy numbers of mutant and
wildtype DNAs and on the circumstances controlling mitochondrial DNA segregation. Muscles from patients with
MERRF or MELAS have some fibers with an excess of mitochondria at their periphery. These fibers are called ragged red
fibers, because their rims are stained red with a mitochondrion-specific staining technique (89). In addition, the affected
mitochondria can be much larger than wildtype mitochondria
and they often have highly ordered arrays of inner membrane
structures called paracrystalline inclusions (Figure 6) (84).
These ordered arrays might result from tight packing of the nuclear encoded inner membrane proteins (90). In summary, a
primary defect in mitochondrial protein synthesis causes secondary defects in the subcellular distribution of mitochondria,
it induces mitochondrial proliferation, it increases the size of
mitochondria and it alters their internal membrane structures.
The affected organs are different when mutations occur in one
of the proteins encoded by mitochondrial DNA. The two most
common diseases are NARP (neuropathy, ataxia and retinitis
pigmentosa) caused by a mutation in a subunit of the F-ATPase
and LHON (Leber’s hereditary optic neuropathy) caused by
mutations in subunits of Complex I or III (84,85). LHON causes
blindness in adults, but there are few other effects. Perhaps optic neurons are selectively affected because of their high metabolic rate or because they place heavy demands on axonal
Many of the known mitochondrial diseases are caused by
mutations in mitochondrial DNA. Few mitochondrial diseases
have thus far been linked to mutations in nuclear DNA. Mutations in mitochondrial DNA are perhaps more readily identified because of the maternal inheritance of mitochondrial
DNA or because of the small size of the mitochondrial genome, which makes it easier to analyze. Mitochondrial DNA
might also accumulate mutations faster than nuclear genes,
because mitochondria have less efficient repair mechanisms.
Mammalian mitochondrial DNA encodes a limited number of
proteins (13 components of the respiratory chain) and the
tRNAs and rRNAs that are required for translation. Although
each of these components contributes to the same process
(oxidative phosphorylation), there is a bewildering variety of
pathologies associated with different kinds of mutations in
mitochondrial DNA (84,85).
Common mitochondrial diseases are MERRF (myoclonic epilepsy with ragged red fibers) and MELAS (mitochondrial
encephalopathy, lactic acidosis and stroke-like episodes),
which are caused by mutations in mitochondrial tRNA or rRNA
genes (88). Most cells carry a mixture of mutant and wildtype
DNAs, but once in a while all wildtype copies of mitochondrial
DNA are lost by segregation. The onset and severity of the disTraffic 2001; 2: 235–244
Figure 6: Paracrystalline inclusions in mitochondria from a
patient with childhood myopathy. This patient has giant abnormal mitochondria (M) with paracrystalline inclusions. These inclusions are observed in many mitochondrial disorders, including
MELAS and MERRF. Often these inclusions have membranes that
are connected to the mitochondrial inner membrane, suggesting
that they are abnormal cristae. Reproduced from (100) with permission from Oxford University Press.
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Griparic and van der Bliek
transport of mitochondria (91). The question then becomes
why the clinical manifestations of NARP and LHON are so different from those of MELAS and MERRF, when in the end both
types of mutations disrupt oxidative phosphorylation.
It is possible that mitochondria respond to mutations affecting protein synthesis by changing other aspects of mitochondrial biogenesis such as transcription of nuclear-encoded
mitochondrial proteins. This would be the case if translation
were directly coupled to a feedback mechanism. Such a
retrograde signaling pathway has been identified in yeast and
in animals cells, but it is not yet known whether these contribute to the pathology of MERRF and MELAS (92). Mutations
in individual proteins, as detected in LHON or NARP, may not
have the same global effect. Their malfunction could be
sensed further downstream, for example at the level of ATP
production, which may trigger a different response, such as
an increase in mitochondrial division.
A new clue in this puzzle came from molecular analysis of a
dominant form of optic atrophy. Patients with dominant optic
atrophy become blind, like patients with LHON (93). The
main differences are that blindness occurs during childhood
instead of later in life, as with LHON, and that the human
disease locus, called OPA1, is a nuclear gene. It was recently
discovered that OPA1 encodes a member of the dynamin
family, called Mgm1 (94,95). The sequence of Mgm1 is
more closely related to bacterial dynamin-like proteins than
to dynamin, suggesting that Mgm1 may have been introduced by the a-proteobacterial progenitor of mitochondria
(96). Mgm1 also has a mitochondrial targeting sequence,
suggesting that the protein is imported, although the localization within mitochondria is still a matter of debate (97–99).
The ongoing debate about the localization of Mgm1 needs
to be resolved before the function of this protein can be adequately addressed (46). In the meantime, however, we can
learn more about the pathology of optic atrophy from mutant
phenotypes that have been observed in yeast, C. elegans
and humans. Loss of Mgm1 causes mitochondria to become
excessively fragmented in yeast (45,99). At a later stage,
mitochondrial DNA is lost, possibly due to missorting (98).
Mitochondrial fragmentation was also observed in a C. elegans Mgm1 mutant (M. D. Zappaterra and A. M. van der
Bliek, unpublished) and in lymphocytes from patients with
dominant optic atrophy (94). It would therefore appear that
loss of Mgm1 function induces mitochondrial division, but
the mechanism by which this occurs has not yet been established. Clearly, much more work needs to be done to determine the mechanisms by which the different mutations affect
mitochondria. We may then begin to understand why different tissues are selectively affected in different mitochondrial
diseases.
Concluding Remarks
The amazing fluidity of mitochondrial shapes raises numerous questions regarding the mechanisms that control these
242
processes. The identification of proteins that affect mitochondrial morphology is just a first step and even that is still in its
infancy. Mitochondrial research thus promises excitement for
many years to come.
Acknowledgments
The authors wish to thank other members of the lab for helpful suggestions
and critical reading of the manuscript. The authors also wish to thank Dr.
Carmen Mannella (NCRR/NIH Resource for the Visualization of Biological
Complexity, Wadsworth Center, Albany, NY) for providing Figure 4 and
many helpful discussions. Work in the authors’ lab is supported by grants
from the NIH (GM58166) and the Cancer Research Coordinating Committee. L.G. is supported by postdoctoral fellowships from the Western States
Affiliates of the American Heart Association and the Jonsson Cancer Center Foundation.
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