Mitochondrial diseases in man and mouse.
Summary (2 min read)
Mitochondrial Genetics
- Mitochondria generate cellular energy in the form of ATP (adenosine triphosphate) by the process of oxidative phosphorylation .
- Modern mitochondria retain a num- ber of features that reflect their endosymbiotic origin.
- (A) and (C) are skeletal muscle samples from a patient with myoclonic epilepsy and ragged-red fiber disease , which is caused by a mutation in the mitochondrially encoded tRNALys gene (38, 39).
- Today’s mtDNA genes are no longer “intelligible” to the nucleocytosolic system and the mammalian mitochondrial genome is functionally stable (9).
- When a mutation arises, cells initially contain a mixture of wild-type and mutant mtDNAs, a state known as heteroplasmy.
Mitochondrial Biology
- The vagaries of mitochondrial genetics are made even more complex by the multiple cellular functions performed by the mitochondri- on.
- Oxygen consumption by the ETC is coupled to ADP phosphorylation by the ATP synthase through the electrochemical gradient, DC (3–5).
- Tfam is important in initiating transcription and in generating the primer from the L-strand transcripts to initiate H-strand DNA replication at OH.
- The positions of representative pathogenic point mutations are shown on the inside of the circle, with the nucleotide position and disease acronym.
- Thus, a marked reduction in mitochondrial energy production and a chronic increase in oxidative stress could theoretically activate the mtPTP and initiate apoptosis.
Mitochondrial Diseases
- As noted earlier, mitochondrial diseases can have a wide variety of inheritance patterns— maternal, Mendelian, and a combination of the two.
- This mutation is invariably heteroplasmic and, when present in a small percentage (,75%) of mtDNAs, it can cause neurogenic muscle weakness, ataxia, and retinitus pigmentosa (NARP).
- Mutations in mitochondrial protein synthesis genes can produce a complex array of symptoms.
- With the loss of this protein, iron accumulates in the mitochondrial matrix, stimulating the conversion of H2O2 to OH z by the Fenton reaction.
- The disease has been linked to two different chromosomal loci, but the responsible genes have not been identified (63, 64).
Somatic mtDNA Mutations in Aging and Cancer
- The delayed onset and progressive course of mitochondrial diseases suggests that mitochondria function may decline with age.
- Somatic mtDNA mutations also occur in the brain.
- These observations have led to the hypothesis that somatic mtDNA mutations accumulate in postmitotic tissues with age as a result of mitochondrial ROS damage.
- This same agerelated decline in OXPHOS could interact with inherited mitochondrial defects, which would account for the delayed onset and progression of mitochondrial diseases.
- These mutations include intragenic deletions (81), missense and chain-termination point mutations (82), and alterations of homopolymeric sequences that result in frameshift mutations (83).
Mouse Models of Mitochondrial Disease
- Patient studies have revealed much about the genetics of mitochondrial disease, but the pathophysiological mechanisms that underlie the complex array of symptoms remain mysterious.
- Thus, Ant12/2 mice are completely deficient in ANT in skeletal muscle, partially deficient in heart, and have normal ANT levels in liver.
- The analysis of heterozygous Sod21/2 mice (91), which exhibit a 50% reduction in MnSOD levels, may pro- 5 MARCH 1999 VOL 283 SCIENCE www.sciencemag.org1486 vide a better model for chronic mitochondrial disease.
Did you find this useful? Give us your feedback
Citations
3,758 citations
Cites background from "Mitochondrial diseases in man and m..."
...To quantitate mito- tures (Himms-Hagen, 1990), and by aging, hypoxia, and various environmental stresses (Wallace, 1999)....
[...]
3,076 citations
3,016 citations
Cites background from "Mitochondrial diseases in man and m..."
...Specific symptoms include forms of blindness, deafness, movement disorders, dementias, cardiovascular disease, muscle weakness, renal dysfunction, and endocrine disorders including diabetes (51, 149, 237, 241, 242)....
[...]
...Mitochondrial DNA (mtDNA): the portion of the mitochondrial genome that currently resides in the matrix of the mitochondrion, as a circular DNA molecule containing the mitochondrial rRNA genes, tRNA genes, and 13 subunits of the mitochondrial oxidative phosphorylation (OXPHOS) enzyme complexes are the only human genetic system that embodies the features necessary to explain the observed characteristics of the common agerelated diseases (237)....
[...]
...The tRNAs, which punctuate the genes, are cleaved out and the mRNAs and are then polyadenylated (237) (Figure 1)....
[...]
...The mitochondrial TCA cycle enzyme aconitase is also an iron-sulfur center protein (234, 235, 237)....
[...]
2,754 citations
Cites background from "Mitochondrial diseases in man and m..."
...The comparison of complete organellar genome sequences is becoming increasingly important for reconstructing the evolutionary relationships of organisms [2, 3, 7, 8], for studying population structure and history [11], including those of humans [6], for identifying forensic materials [10], and for understanding the inheritance of certain human diseases [12]....
[...]
1,999 citations
Cites background from "Mitochondrial diseases in man and m..."
...ROS-related damage has been implicated in aging, cancer, and ischemia-reperfusion injury of the heart and brain (Balaban et al., 2005; Wallace, 1999)....
[...]
References
8,757 citations
6,007 citations
5,128 citations
4,095 citations
2,374 citations
Related Papers (5)
Frequently Asked Questions (16)
Q2. What are the important aspects of mitochondrial OXPHOS for disease pathogenesis?
Three of the more important aspects of mitochondrial OXPHOS for disease pathogenesis are: (i) energy production, (ii) generation of reactive oxygen species (ROS), and (iii) regulation of programmed cell death, or apoptosis.
Q3. What is the role of mitochondria in the development of cellular energy?
Mitochondria generate cellular energy in the form of ATP (adenosine triphosphate) by the process of oxidative phosphorylation (OXPHOS).
Q4. What is the effect of inhibition of OXPHOS on mitochondria?
inhibition of OXPHOS not only reduces energy produc-tion, but also elevates ROS production with an associated increase in damage to the mitochondria and mtDNA.
Q5. What is the effect of chronic ROS exposure on mitochondria?
Chronic ROS exposure can result in oxidative damage to mitochondrial and cellular proteins, lipids, and nucleic acids, and acute ROS exposure can inactivate the ironsulfur (Fe-S) centers of ETC complexes I, II, and III, and TCA cycle aconitase, resulting in shutdown of mitochondrial energy production (3, 4 ).
Q6. How can a mitochondrial mtDNA be converted to OHz?
in the presence of reduced transition metals, can also be converted to the highly reactive hydroxyl radical (OHz) by the Fenton reaction.
Q7. What are the other diseases that arise from nucleocytoplasmic interactions?
Other diseases that arise from nucleocytoplasmic interactions include the autosomal dominant-progressive external ophthalmoplegia (AD-PEO), the mtDNA depletion syndrome, and the MNGIE syndrome.
Q8. What is the current state of the mitochondrial genome?
Today’s mtDNA genes are no longer “intelligible” to the nucleocytosolic system and the mammalian mitochondrial genome is functionally stable (9).
Q9. What is the cause of the somatic mtDNA rearrangements in the heart?
Patients with chronic ischemic heart disease, which is associated with cyclic bursts of mitochondrial ROS during ischemia and reperfusion (76), have been found to harbor 8 to 2000 times more mtDNA deletions in the heart than age-matched controls (77).
Q10. What is the purpose of the CAPR mtDNA mutation in mice?
the CAPR mtDNA mutation has been introduced into mouse female embryonic stem (ES) cells by cybrid transfer, with subsequent injection of the mutant ES cells into blastocysts, and generation of chimeric females.
Q11. What is the way to transfer a mutant mtDNA to a healthy cell?
Cultured cells from patients harboring either of these mutations have reduced levels of mitochondrial protein synthesis and complex The authorand IV activities, and these defects can be transferred along with the mutant mtDNA in cybrid transfer experiments (43–45).
Q12. What are the first mitochondrial diseases to be understood at the molecular level?
The first mitochondrial diseases to be understood at the molecular level were the maternally inherited Leber’s hereditary optic neuropathy (LHON), a sudden-onset blindness resulting from a mitochondrial DNA (mtDNA) missense mutation (6), and a spontaneously occurring group of neuromuscular diseases, now classified as chronic progressive external ophthalmopelia (CPEO) and the Kearns-Sayre Syndrome (KSS), which result from mtDNA deletions (7 ) (Fig. 2).
Q13. What are the common clinical features of mitochondrial encephalomyopathies?
Although the mitochondrial encephalomyopathies frequently share certain clinical features such as RRFs, specific mutations are often associated with specific clinical manifestations.
Q14. What is the role of the mtPTP in mitochondrial disease?
a marked reduction in mitochondrial energy production and a chronic increase in oxidative stress could theoretically activate the mtPTP and initiate apoptosis.
Q15. What is the extent of mtDNA rearrangements in mice?
An analogous agerelated accumulation of somatic mtDNA rearrangements also occurs in mouse tissues (73), the extent of which is proportional to life-span rather than absolute time.
Q16. What is the first indication that mitochondria may play a role in pathogenesis?
One of the first indications that mitochondria may play a role in pathogenesis was the report nearly 40 years ago of a patient with hypermetabolism whose skeletal muscle contained large numbers of abnormal mitochondria, a condition now known as mitochondrial myopathy (Fig. 1) (1).