Scheffler Immo E. Mitochondria

THE DYNAMICS OF MITOCHONDRIAL MORPHOLOGY 51

tion of the bud emergence from the zygote (83) . To interpret these ﬁ ndings,

many questions remain to be answered about the nature of the attachment of

the mtDNA to either (a) structures within the matrix that restrict diffusion or

(b) attachment sites that are connected to cytoskeletal structures on the

outside.

As illustrated by the above discussion, genetic approaches are a powerful

means of discovering genes in yeast encoding functions related to mitochon-

drial morphology, segregation, and stability. Mutants such as mgm1 (mitochon-

drial genome maintenance (84, 85) ) and the series of yme mutants (yeast

mitochondrial DNA escape (86) ) represent additional examples that still pose

major challenges for the future. No other organism is comparably advanced

and genetically more tractable than yeast. However, while yeast has been the

model system par excellence for understanding many fundamental aspects of

the biology of mitochondria, other future problems related to cell differentia-

tion and development may not have counterparts in yeast biology.

3.3.3 During Cell Differentiation

Developmentally regulated fusion of mitochondria has been described in a

limited number of mammalian tissues, where its functional signiﬁ cance is

obscure. It is observed in many lower eukaryotes (protists, fungi, algae; reviewed

by in reference 74 ) and in insect spermatogenesis, with much emphasis on

Drosophila (24, 87, 88) . Cytological and electron microscopic descriptions (e.g.,

reference 88 ) have documented dramatic morphological changes associated

with spermatid differentiation after the completion of meiosis, and the behav-

ior of mitochondria during this period has attracted special attention. All

mitochondria ﬁ rst aggregate next to the haploid nucleus, and then appear to

fuse into two giant mitochondria. These two giant mitochondria remain inti-

mately associated in a spherical structure called a Nebenkern. The mitochon-

drial membranes form a series of concentric layers resembling an onion in

cross section. When the axoneme is formed and ﬂ agellar growth procedes, the

two mitochondria separate from each other and elongate along the axoneme.

The juxtaposition of mitochondria and axoneme along the long axis assures

an optimum transfer of ATP to the dynein motors of the axoneme to support

ﬂ agellar movement. The hydrodynamics of the sperm tail motion is optimized

by a decreasing thickness along its length, and this is achieved by a gradual

decrease in mitochondrial size (diameter) in the sheath, while the diameter of

the axoneme remains constant. The entire process has many facets for which

molecular details remain to be unraveled.

The use of Drosophila as a model organism in genetics and developmental

biology has led to the accumulation of a large collection of mutants. Among

the male sterility mutants, a mutant termed fzo (fuzzy onions) was recognized

to have a defect in the mitochondrial fusions leading to Nebenkern formation.

As a consequence, postmeiotic sperm differentiation is arrested. In a typical

52 STRUCTURE AND MORPHOLOGY. INTEGRATION INTO THE CELL

illustration of the power of the “ reverse genetic approach, ” Hales and Fuller

(89) have mapped, cloned, and sequenced the gene, derived a protein sequence,

and from it predicted the existence of a transmembrane GTPase. This protein

is present on spermatid mitochondria during the relevant period when fusion

takes place, as determined by indirect immunoﬂ uorescene microscopy. Homo-

logues of the gene have been detected in mammals, nematodes, and yeast, and

they constitute a novel family of multidomain GTPases. The biological func-

tion of this protein is of special interest, because Rab GTPases have been

well - characterized as the enzymes that control the assembly of the SNARE

complex required for vesicle docking in the secretory pathway (90) . As

described above, the original identiﬁ cation of the Fzo gene from Drosophila

has stimulated much research in yeast, where genetic, biochemical, and cyto-

logical experiments are technically easier than with Drosophila gonads.

A comprehensive review under the provocative title “ Sexuality of Mito-

chondria ” by Kawano et al. (74) contains an expertly written account of mito-

chondrial fusions and recombination between mitochondrial genomes in the

life cycle of the true slime mold Physarum polycephalum . In this organism,

mitochondrial fusions are not serving in morphological rearrangements as

required in spermatogenesis. The authors emphasize recombination ( “ mito-

chondrial meiosis ” ) and view the process in the broader context of the evolu-

tion and manifestations of sex. This view is reinforced by the ﬁ nding that only

strains of P. polycephalum harboring a unique mitochondrial plasmid can

display mitochondrial fusion, and the mitochondrial fusion - promoting (mF)

plasmid may be representative of parasitic, selﬁ sh genes on plasmids that have

been proposed on theoretical grounds to have played a role in the early stages

in the evolution of sex.

The review contains a broad introduction to mitochondrial fusion, and the

formation of giant mitochondria and reemphasizes the distinction between

random fusions of mitochondria as observed in animal cells and periodic

fusions as observed in protists, algae, and fungi, where it may have a much

greater genetic signiﬁ cance. It is relevant that fungi such as Saccharomyces

cerevisiae and Physarum polycephalum have mitochondrial nucleods (referred

to as mt - nuclei in reference 74 ), and therefore it becomes an issue whether

these mt - nuclei also “ fuse. ” From the discussion in an earlier section, it appears

that the mitochondrial genomes of two mating partners in a yeast mating

remain segregated for some time after fusion, although recombination has

indeed been observed in yeast. The true slime mold has a complicated life cycle

during which programmed mitochondrial fusion occurs during two phases (see

reference 74 for details). A germinating haploid spore gives rise to myx-

amoeba, which can fuse to form a zygote from which a plasmodium develops.

During the earliest stages of plasmodium formation, mitochondrial fusion and

fusion of mt - nuclei also occur in mF

+

strains. Another series of mF plasmid -

dependent mitochondrial fusions occur during sporulation which can be

induced in the mature plasmodium. The large amount of mtDNA in P. poly-

cephalum mitochondria facilitiates the observation of mt - nuclei by DAPI

THE DYNAMICS OF MITOCHONDRIAL MORPHOLOGY 53

staining, and the process of sporulation can be synchronized by an illumination

cycle. A detailed analysis of mtDNA replication and of mt - nuclei behavior

thus becomes possible, and its description can be found in the original papers

by Kawano and colleagues. Many intricate details require attention for under-

standing the mating - type system of P. polycephalum and the genetic control

of mtDNA transmission. Kawano and colleagues take advantage of restriction

enzyme polymorphisms (RFLPs) in the mtDNA of various strains to do mito-

chondrial genetics.

The Mif

+

and Mif

−

phenotypes with respect to mitochondrial fusion dis-

covered ﬁ rst were ascribed to the existence of a single transmissible factor

that eventually was identiﬁ ed as an ∼ 16 - kb mitochondrial plasmid. Plasmid

sequences can also be found integrated into the mtDNA, and even mif

−

strains

were found to have certain integrated plasmid sequences. It was concluded

that the missing sequences were responsible for the Mif

+

phenotype. A further

analysis of the mitochondrial fusion frequencies in mif

+

strains also established

the presence of nuclear alleles controlling the frequency of mitochondrial

fusion, but their precise nature remains to be elucidated.

The linear mF plasmid has been sequenced. Ten potential ORFs have been

identiﬁ ed, but deduced amino acid sequences do not show signiﬁ cant homol-

ogy with any amino acid sequences in the SWISS - PROT database, except for

one which has been tentatively identiﬁ ed as a DNA polymerase (91) . Closely

related DNA polymerase sequences have been found on other linear mito-

chondrial plasmids.

Several important biological questions related to the mF plasmid can be

raised, but answers are not available or incomplete. Some of these have been

elaborated in the section on mitochondrial plasmids in Chapter 4 (Section

4.1.6 ). To restate them brieﬂ y here:

1. The replication of a linear plasmid DNA poses special problems that can

be overcome by the existence of terminal inverted repeat sequences

(TIRs) and mechanisms for replication initiation and priming.

2. The nature of the gene products encoded by the plasmid is of interest to

answer several questions.

3. How is the plasmid maintained in the mitochondria?

4. What functions are necessary to promote mitochondrial fusions?

5. How do plasmid sequences become integrated into mtDNA, and what

are the biological consequences of such a recombination?

Space limitations preclude a pursuit of progress in this subject over the last

decade. The interested reader can ﬁ nd an entry into this literature from a

limited number of recent publications (92) .

In summary, the discussion of developmentally regulated mitochondrial

fusions is not intended to be exhaustive, but examples have been chosen to

illustrate the potential rationale for the evolution of mechanisms of fusion. It

54 STRUCTURE AND MORPHOLOGY. INTEGRATION INTO THE CELL

is conceivable that mitochondrial fusions were originally part of the overall

process of sexual reproduction, including genetic recombination of all genomes

in the organisms. In organisms such as mammals, where recombination between

mt genomes is no longer observed at any signiﬁ cant frequency, the rationale

for fusion of mitochondria in ﬁ broblasts is less obvious, unless one views it as

the simple reverse of ﬁ ssion, where ﬁ ssion is required for mitochondrial

multiplication. The cell - speciﬁ c and tissue - speciﬁ c regulated fusion seen in

these organisms may represent special adaptations of the more primitive

mechanisms observed in lower eukaryotes.

3.3.4 Turnover and Degradation

In Chapter 4 a summary of our current understanding of regulated protein

degradation in mitochondria is presented. The emphasis there is on selective

protein degradation by intra - mitochondrial ATP - dependent proteases (93 – 95) .

In the present section, only a brief account of what is known about turnover

of the entire organelle will be presented. In general, the bulk of mitochondrial

proteins are quite stable over prolonged periods of time. In mammalian

cells, half - lives are measured in days, if not weeks. In yeast, a recent study

found that mitochondria labeled with imported GFP (mito - GFP) did not

become signiﬁ cantly altered over a period of 7 hours even when the yeast

cells were shifted from aerobic conditions to anaerobic, glucose - repressed

conditions.

Indirect evidence for some mechanism related to turnover can be deduced

from the age - dependent onset of neuropathies and myopathies and the associ-

ated increase in the fraction of mutated mitochondrial genomes in subpopula-

tions of muscle or neuronal cells. The time scale for such a change in the

genetic and biochemical properties of mitochondrial populations is still not

well - deﬁ ned, and it may be very difﬁ cult to measure precisely in vivo over a

period of years.

There are some physiological and perhaps pathological conditions where

cells are forced to resort to extreme measures to stay alive. Under prolonged

and severe starvation, many cells initiate a process referred to as autophagy

(96 – 98) . Autophagy can also be induced by mitochondrial dysfunction. Subcel-

lular organelles can then ﬁ nd themselves engulfed by lysosomes (in animal

cells) or by the vacuole (in yeast and plant cells), and this internal degradation

is presumably initiated to mobilize resources for the most essential functions

for survival. Alternatively, autophagy is one mechanism for quality control in

which the entire damaged organelle, rather than individual proteins and other

components, is removed from the cell. Mitophagy, speciﬁ cally involving mito-

chondria, is triggered by damage due to oxidative stress or from mutations in

mtDNA (99 – 101) . Understanding these mechanisms, and perhaps their failure,

will undoubtedly contribute much to our understanding of apoptosis, aging,

and neurodegeneration.

THE DYNAMICS OF MITOCHONDRIAL MORPHOLOGY 55

3.3.5 Mitochondrial Alterations in Apoptosis

A special problem involving mitochondria, morphological alterations in their

structure, and ultimately their degradation arises in the discussion of apoptosis

and certain pathological conditions. This subject will be discussed in more

detail in a later chapter. Earlier studies had placed the emphasis on permeabil-

ity changes of the outer membrane and the release of proteins from the IMS.

It is now becoming apparent that morphological changes and fragmentation

of mitochondria are intimately associated with the apoptotic pathway at rela-

tively early stages. The perturbation (e.g., by RNA interference or mutations)

of the ﬁ ssion and fusion complexes can have pronounced effects on the activity

of pro - apoptotic or anti - apoptotic factors (59) .

3.3.6 Unsolved Problems for the Future

There are several broad areas in which more information is needed, and future

progress can be expected. Such progress is likely to be more rapid in organisms

in which genetic approaches are possible such that mitochondrial morphology

and behavior can be manipulated or modulated. Yeast is the organism of

choice here. It is anticipated that interesting new proteins and their genes will

have homologues in other organisms, allowing the information to be general-

ized or extended in other systems. The fruit ﬂ y Drosophila may be a second

experimental genetic system in which to study mitochondria in the context

of development and differentiation of specialized cells. Other problems may

be unique to vertebrates, for example, and even to speciﬁ c cell types and

tissues.

Among the major problems, one could list the following:

1. What controls the total surface area and hence the elaboration of cristae

in a mitochondrion in a given tissue? Why do the cristae have such

unusual morphologies in some mitochondria?

2. Is the matrix of mitochondria organized in a way that controls the

position of the mtDNA, the location of protein synthesis, and perhaps

even the shape of mitochondria by means of internal structural

elements?

3. What are the structures (protein domains) on the surface of mitochon-

dria capable of interacting with diverse cytoskeletal elements via molec-

ular motors? How do such interactions contribute to the changing shape

of mitochondria, to their movement within the cell, and their accumula-

tion in subcellular regions?

4. What mechanisms control division and fusion of mitochondria? The

fact that two membranes are involved adds complexity. What controls

the speciﬁ city and the timing, with reference to cell division and

differentiation?

56 STRUCTURE AND MORPHOLOGY. INTEGRATION INTO THE CELL

REFERENCES

1 . Yost , H. J. and Lindquist , S. ( 1986 ) Cell 45 , 185 – 193 .

2 . Matsuyama , S. , Llopis , J. , Dveraux , Q. L. , Tsien , R. Y. , and Reed , J. C. ( 2000 ) Nature

Cell Biol. 2 , 318 – 325 .

3 . Goldstein , J. C. , Munoz - Pinedo , C. , Ricci , J. E. , Adams , S. R. , Kelekar , A. , Schuler , M. ,

Tsien , R. Y. , and Green , D. R. ( 2005 ) Cell Death Differ. 12 , 453 – 462 .

4 . Steinert , M. and Steinert , G. ( 1960 ) Exp. Cell Res 19 , 421 – 424 .

5 . Perkins , G. , Renken , C. , Martone , M. E. , Young , S. J. , Ellisman , M. , and Frey , T. ( 1997 )

J. Struct. Biol. 119 , 260 – 272 .

6 . Mannella , C. A. , Marko , M. , and Buttle , K. ( 1997 ) Trends Biochem. Sci. 22 , 37 – 38 .

7 . Mannella , C. A. , Pfeiffer , D. R. , Bradshaw , P. C. , Moraru , I. , Slepchenko , B. , Loew ,

L. M. , Hsieh , C. E. ,

Buttle , K. , and

Marko , M. ( 2001 ) IUBMB Life 52 , 93 – 100 .

8 . Mannella , C. A. ( 2000 ) J. Bioenerg. Biomembr. 32 , 1 – 4 .

9 . Frey , T. G. and Mannella , C. A. ( 2000 ) Trends Biochem. Sci. 25 , 319 – 324 .

10. Frey , T. G. , Renken , C. W. , and Perkins , G. A. ( 2002 ) Biochim. Biophys. Acta 1555 ,

196 – 203 .

11. Perkins , G. A. and Frey , T. G. ( 2000 ) Micron 31 , 97 – 111 .

12. Mannella , C. A. ( 2006 ) Biochim. Biophys. Acta 1762 , 140 – 147 .

13. Renken , C. , Siragusa , G. , Perkins , G. , Washington , L. , Nulton , J. , Salamon , P. , and Frey ,

T. ( 2002 ) J. Struct. Biol. 138 , 137 .

14. Ponnuswamy , A. , Nulton , J. , Mahaffy , J. M. , Salamon , P. , Frey , T. G. , and Baljon , A. R.

( 2005 ) Phys. Biol. 2 , 73 – 79 .

15. John , G. B. , Shang , Y. , Li , L. , Renken , C. , Mannella , C. A. ,

Selker , J. M. ,

Rangell , L. ,

Bennett , M. J. , and Zha , J. ( 2005 ) Mol. Biol. Cell 16 , 1543 – 1554 .

16. Bustos , D. M. and Velours , J. ( 2005 ) J. Biol. Chem. 280 , 29004 – 29010 .

17. Arselin , G. , Vaillier , J. , Salin , B. , Schaeffer , J. , Giraud , M. F. , Dautant , A. , Brethes , D. ,

and Velours , J. ( 2004 ) J. Biol. Chem. 279 , 40392 – 40399 .

18. Paumard , P. , Vaillier , J. , Coulary , B. , Schaeffer , J. , Soubannier , V. , Mueller , D. M. ,

Brethes , D. , Di Rago , J. P. , and Velours , J. ( 2002 ) EMBO J. 21 , 221 – 230 .

19. Scorrano , L. ( 2005 ) J. Bioenerg. Biomembr. 37 , 165 – 170 .

20. Perfettini , J. L. , Roumier , T. , and Kroemer , G. ( 2005 ) Trends Cell Biol. 15 , 179 – 183 .

21. Vogel , F. , Bornhovd , C. , Neupert , W. , and Reichert , A. S. ( 2006 ) J. Cell Biol. 175 ,

237 – 247 .

22.

Hoffman , H. P. and Avers , C. J. ( 1973 )

Science 181 , 749 – 751 .

23. Stevens , B. ( 1981 ) Mitochondrial structure . In Strathern , J. N. , Jones , E. W. , and

Broach , J. R. , editors. The Molecular Biology of the Yeast Saccharomyces, Life Cycle

and Inheritance , Cold Spring Harbor Laboratory Press , Cold Spring Harbor, NY .

pp. 471 – 504 .

24. Fawcett , D. W. ( 1981 ) Mitochondria . In The Cell , W. B. Saunders , Philadelphia .

25. Hackenbrock , C. R. , Chazotte , B. , and Gupte , S. S. ( 1986 ) J. Bioenerg. Biomembr. 18 ,

331 – 368 .

26. Chazotte , B. and Hackenbrock , C. R. ( 1991 ) J. Biol. Chem. 266 , 5973 – 5979 .

27. Lipowsky , R. ( 1991 ) Nature 349 , 475 – 481 .

28. Heggeness , M. H. , Simon , M. , and Singer , S. J. ( 1978 ) Proc. Natl. Acad. Sci. USA 75 ,

3863 – 3866 .

29. Ball , E. H. and Singer , S. J. ( 1982 ) Proc. Natl. Acad. Sci. USA 79 , 123 – 126 .

30. Johnson , L. V. , Walsh , M. L. , and Chen , L. B. ( 1980 ) Proc. Natl. Acad. Sci. USA 77 ,

990 – 994 .

31. Chen , L. B. ( 1988 ) Annu. Rev. Cell Biol. 4 , 155 – 181 .

32. Reers , M. , Smiley , S. T. , Mottola - Hartshorn , C. , Chen , A. , Lin , M. , and Chen , L. B.

( 1995 ) Methods Enzymol. 260 , 406 – 417 .

33. Bereiter - Hahn , J. ( 1990 ) Int. Rev. Cytol. 122 , 1 – 64 .

34. Bereiter - Hahn , J. and Voth , M. ( 1994 ) Microsc. Res. Tech. 27 , 198 – 219 .

35. Nunnari , J. , Marshall , W. F. , Straight , A. , Murray , A. , Sedat , J. W. , and Walter , P. ( 1997 )

Mol. Biol. Cell 8 , 1233 – 1242 .

36. Rizzuto , R. , Pinton , P. , Carrington , W. , Fay , F. S. ,

Fogarty

, K. E. , Lifshitz , L. M. , Tuft ,

R. A. , and Pozzan , T. ( 1998 ) Science 280 , 1763 – 1766 .

37. Yadava , N. and Schefﬂ er , I. E. ( 2004 ) Mitochondrion 4 , 1 – 12 .

38. Szabadkai , G. , Simoni , A. M. , Bianchi , K. , De Stefani , D. , Leo , S. , Wieckowski , M. R. ,

and Rizzuto , R. ( 2006 ) Biochim. Biophys. Acta. 1763 , 442 – 429 .

39. Goetz , J. G. and Nabi , I. R. ( 2006 ) Biochem Soc. Trans. 34 , 370 – 373 .

40. Chang , D. T. , Honick , A. S. , and Reynolds , I. J. ( 2006 ) J. Neurosci. 26 , 7035 – 7045 .

41. Chen , H. and Chan , D. C. ( 2006 ) Curr. Opin. Cell Biol. 18 , 453 – 459 .

42. Overly , C. C. , Rieff , H. I. , and Hollenbeck , P. J. ( 1996 ) J. Cell Sci. 109 , 971 – 980 .

43. Morris , R. L. and Hollenbeck , P. J. ( 1995 ) J. Cell Biol. 131 , 1315 – 1326 .

44. Lee , K. D. and Hollenbeck , P. J. ( 1995 ) J. Biol. Chem. 270 , 5600 – 5605 .

45.

Morris , R. L. and Hollenbeck , P. J. ( 1993 ) J. Cell Sci. 104 , 917 – 927 .

46. Hollenbeck , P. J. ( 2005 ) Neuron 47 , 331 – 333 .

47. Hollenbeck , P. J. and Saxton , W. M. ( 2005 ) J. Cell Sci. 118 , 5411 – 5419 .

48. Chada , S. R. and Hollenbeck , P. J. ( 2003 ) J. Exp. Biol. 206 , 1985 – 1992 .

49. Miller , K. E. and Sheetz , M. P. ( 2004 ) J. Cell Sci. 117 , 2791 – 2804 .

50. Berger , K. H. and Yaffe , M. P. ( 1996 ) Experientia 52 , 1111 – 1116 .

51. Yaffe , M. P. ( 1999 ) Science 283 , 1493 – 1497 .

52. Jensen , R. E. ( 2005 ) Curr. Opin. Cell Biol. 17 , 384 – 388 .

53. Meeusen , S. L. and Nunnari , J. ( 2005 ) Curr. Opin. Cell Biol. 17 , 389 – 394 .

54. Osteryoung , K. W. and Nunnari , J. ( 2003 ) Science 302 , 1698 – 1704 .

55. Shaw , J. M. and Nunnari , J. ( 2002 ) Trends Cell Biol. 12 , 178 .

56. Altmann , K. and Westermann , B. ( 2005 ) Mol. Biol. Cell 16

, 5410 – 5417 .

57. Rube , D. A. and Van der Bliek , A. M. ( 2004 ) Mol. Cell Biochem. 256 – 257 , 331 – 339 .

58. Anesti , V. and Scorrano , L. ( 2006 ) Biochim. Biophys. Acta 1757 , 692 – 699 .

59. Okamoto , K. and Shaw , J. M. ( 2005 ) Annu. Rev. Genet. 39 , 503 – 536 .

59a. Hoppins , S. , Lackner , L. , and Nunnari , J. ( 2007 ) Annu. Rev. Biochem. 76 , 751 – 780 .

60. Schrader , M. ( 2006 ) Biochim. Biophys. Acta 1763 , 531 – 541 .

61. Kuroiwa , T. , Kuroiwa , H. , Sakai , A. , Takahashi , H. , Toda , K. , and Itoh , R. ( 1998 ) Int.

Rev. Cytol. 181 , 1 – 41 .

REFERENCES 57

58 STRUCTURE AND MORPHOLOGY. INTEGRATION INTO THE CELL

62. Song , B. D. and Schmid , S. L. ( 2003 ) Biochemistry 42 , 1369 – 1376 .

63. Bleazard , W. , McCaffery , J. M. , King , E. J. , Bale , S. , Mozdy , A. , Tieu , Q. , Nunnari , J. ,

and Shaw , J. M. ( 1999 ) Nat. Cell Biol. 1 , 298 – 304 .

64. Kelly , R. B. ( 1995 ) Nature 374 , 116 – 117 .

65. Olichon , A. , Guillou , E. , Delettre , C. , Landes , T. , Arnaune - Pelloquin , L. , Emorine , L. J. ,

Mils , V. , Daloyau , M. , Hamel , C. , Amati - Bonneau , P. , Bonneau , D. , Reynier , P. , Lenaers ,

G. , and Belenguer , P. ( 2006 ) Biochim. Biophys. Acta 1763 , 500 – 509 .

66. Sesaki , H. , Dunn , C. D. , Iijima , M. , Shepard , K. A. , Yaffe , M. P. , Machamer , C. E. , and

Jensen , R. E. ( 2006 ) J. Cell Biol. 173 , 651 – 658 .

67. Meeusen , S. , McCaffery , J. M. , and Nunnari , J. ( 2004 ) Science

305

, 1747 – 1752 .

68. Koshiba , T. , Detmer , S. A. , Kaiser , J. T. , Chen , H. , McCaffery , J. M. , and Chan , D. C.

( 2004 ) Science 305 , 858 – 862 .

69. Amutha , B. , Gu , Y. , and Pain , D. ( 2004 ) Biochem. J. 381 , 19 – 23 .

70. Olichon , A. , Baricault , L. , Gas , N. , Guillou , E. , Valette , A. , Belenguer , P. , and Lenaers ,

G. ( 2003 ) J. Biol. Chem. 278 , 7743 – 7746 .

71. Ishihara , N. , Fujita , Y. , Oka , T. , and Mihara , K. ( 2006 ) EMBO J. 25 , 2966 – 2977 .

72. Jeyaraju , D. V. , Xu , L. , Letellier , M. C. , Bandaru , S. , Zunino . R. , Berg , E. A. , McBride ,

H. M. , and Pellegrini , L. ( 2006 ) Proc. Natl. Acad. Sci. USA 103 , 18562 – 18567 .

73. Escobar - Henriques , M. , Westermann , B. , and Langer , T. ( 2006 ) J. Cell Biol. 173 ,

645 – 650 .

74. Kawano

, S. , Takano

, H. , and Kuroiwa , T. ( 1995 ) Int. Rev. Cytol. 161 , 49 – 110 .

75. Yaffe , M. P. ( 1995 ) Methods Enzymol. 260 , 447 – 453 .

76. Burgess , S. M. , Delannoy , M. , and Jensen , R. E. ( 1994 ) J. Cell. Biol. 126 , 1361 – 1373 .

77. Dimmer , K. S. , Jakobs , S. , Vogel , F. , Altmann , K. , and Westermann , B. ( 2005 ) J. Cell

Biol. 168 , 103 – 115 .

78. Dimmer , K. S. , Fritz , S. , Fuchs , F. , Messerschmitt , M. , Weinbach , N. , Neupert , W. , and

Westermann , B. ( 2002 ) Mol. Biol. Cell 13 , 847 – 853 .

79. Stewart , L. C. and Yaffe , M. P. ( 1991 ) J. Cell. Biol. 115 , 1249 – 1257 .

80. Miyakawa , I. , Aoi , H. , Sando , N. , and Kuroiwa , T. ( 1984 ) J. Cell. Sci. 66 , 21 – 38 .

81. Birky , C. W. , Jr . ( 1994 ) J. Hered. 85 , 355 – 365 .

82. Birky , C. W. , Jr . ( 1995 ) Proc. Natl. Acad. Sci. USA 92 , 11331 – 11338 .

83. Azpiroz

, R. and Butow , R. A. ( 1995 )

Methods Enzymol. 260 , 453 – 465 .

84. Jones , B. A. and Fangman , W. L. ( 1992 ) Genes Dev. 6 , 380 – 389 .

85. Chen , X. - J. , Guan , M. - X. , and Clark - Walker , G. D. ( 1993 ) Nucleic Acids Res. 21 ,

3473 – 3477 .

86. Thorsness , P. E. and Weber , E. R. ( 1996 ) Int. Rev. Cytol. 165 , 207 – 234 .

87. Fuller , M. T. ( 1993 ) Spermatogenesis . In Bate , M. and Martinez - Arias , A. , editors.

The Development of Drosophila , Cold Spring Harbor Press , Cold Spring Harbor,

NY , pp. 71 – 147 .

88. Tokuyasu , K. T. ( 1974 ) Exp. Cell Res. 84 , 239 – 250 .

89. Hales , K. G. and Fuller , M. T. ( 1997 ) Cell 90 , 121 – 129 .

90. Pfeffer , S. R. ( 1996 ) Annu. Rev. Cell Dev. Biol. 12 , 2351 – 2359 .

91. Takano , H. , Kawano , S. , and Kuroiwa , T. ( 1994 ) Curr. Genet. 25 , 252 – 257 .

92. Sakurai , R. , Nomura , H. , Moriyam , Y. , and Kawano , S. ( 2004 ) Curr. Genet. 46 ,

103 – 114 .

93. Augustin , S. , Nolden , M. , Muller , S. , Hardt , O. , Arnold , I. , and Langer , T. ( 2004 ) J. Biol.

Chem. 280 , 2691 – 2699 .

94. Bota , D. A. , Ngo , J. K. , and Davies , K. J. ( 2005 ) Free Radic. Biol. Med. 38 ,

665 – 677 .

95. Bota , D. A. and Davies , K. J. ( 2001 ) Mitochondrion 1 , 33 – 49 .

96. Seglen , P. O. , Berg , T. O. , Blankson , H. , Fengsrud , M. , Holen , I. , and Stromhaug , P. E.

( 1996 ) Adv. Exp. Med. Biol. 389 , 103 – 111 .

97. Aubert , S. , Gout , E. , Bligny , R. , Marty - Mazars , D. , Barrieu , F. , Alabouvette , J. , Marty ,

F. , and Douce , R. ( 1996 ) J. Cell Biol. 133 , 1251 – 1263 .

98. Scott , S. V. , Hefner - Gravink , A. , Morano , K. A. , Noda

, T. , Ohsumi , Y. , and Klionsky , D.

J. ( 1996 ) Proc. Natl. Acad. Sci. USA 93 , 12304 – 12308 .

99. Priault , M. , Salin , B. , Schaeffer , J. , Vallette , F. M. , Di Rago , J. P. , and Martinou , J. C.

( 2005 ) Cell Death Differ. 12 , 1613 – 1621 .

100. Gu , Y. , Wang , C. , and Cohen , A. ( 2004 ) FEBS Lett. 577 , 357 – 360 .

101. Terman , A. and Brunk , U. T. ( 2004 ) Exp. Gerontol. 39 , 701 – 705 .

REFERENCES 59

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4

Mitochondria, Second Edition, by Immo E. Schefﬂ er

BIOGENESIS OF MITOCHONDRIA

Summary

An estimated 800 – 1500 proteins are found in mitochondria at a relative abundance

that varies from tissue to tissue. Of those, only 13 are encoded by the mitochondrial

genome, but each is essential for oxidative phosphorylation. The biogenesis of mito-

chondria therefore includes several major themes. First, mtDNA has to be character-

ized and a mechanism for its replication has to be deﬁ ned. Second, the mtDNA has

to be transcribed, and the long primary transcripts have to be processed to yield two

rRNAs, 22 tRNAs, and 13 mRNAs (in mammalian mitochondria). Third, a transla-

tional machinery for initiation and elongation of proteins exists in the mitochondrial

matrix. The resulting proteins have to be inserted into the inner mitochondrial mem-

brane, probably coupled to the assembly of the complexes of the oxidative phos-

phorylation system. Fourth, the vast majority of mitochondrial proteins are made in

the cytosol. They must contain a signal for import into mitochondria, but there must

be additional mechanisms assuring that each protein reaches its ﬁ nal, distinct local-

ization: in the outer membrane, in the intermembrane space, in the inner membrane,

and in the matrix. After the initial recognition by the TOM complex in the outer

membrane, proteins are shuttled to complexes in the inner membrane (TIM) for

distribution to their ﬁ nal destination. The import requires a membrane potential.

Some proteins are subject to post - import processing by proteases. Turnover of

proteins in mitochondria, or turnover of whole mitochondria by autophagy are

processes under active investigation.

In many organisms (e.g., plants and fungi), some or all tRNAs have to be imported

into the mitochondrial matrix from the cytosol. In many organisms RNA editing

occurs: The original transcript is modiﬁ ed before it is translated into protein. This

may involve a simple deamination (C to U) at selected sites, or it may include very

substantial insertions or deletions of uridine tracts into the mRNA (e.g., in

trypanosomes).

Scheffler Immo E. Mitochondria

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