Mitochondrial medicine – recent advances

Graff, Caroline; Clayton, David A.; Larsson, Nils‐Göran

doi:10.1046/j.1365-2796.1999.00514.x

Cited by 70 publications

(23 citation statements)

References 105 publications

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“…This process occurs in mitochondria in which mitochondrial (mt)DNA encodes for essential subunits of the respiratory chain (20,55). Even under physiological conditions, there are large variations in the number of deletions in mtDNA due to its specific structure, function, and location.…”

Section: Epithelium; Energy Metabolismmentioning

confidence: 99%

“…mtDNA mutates 10 times as frequently as nuclear DNA, has no protective histones or repair system, and is constantly exposed to free radicals generated during the cell's normal oxidative phosphorylation process (25,26). When mtDNA mutations occur in muscle or nerve cells, this results in reduced energy production translated into obvious clinical manifestations (20,55). However, similar defects may be far more difficult to detect when they occur in the intestinal epithelium, particularly under inflammatory conditions.…”

Section: Epithelium; Energy Metabolismmentioning

confidence: 99%

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Paradoxical decrease of mitochondrial DNA deletions in epithelial cells of active ulcerative colitis patients

Fukushima¹,

Fiocchi²

2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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Fukushima, Kouhei, and Claudio Fiocchi. Paradoxical decrease of mitochondrial DNA deletions in epithelial cells of active ulcerative colitis patients. Am J Physiol Gastrointest Liver Physiol 286: G804-G813, 2004; 10.1152/ajpgi.00398.2003.-Ulcerative colitis (UC) is a condition characterized by chronic inflammation targeted at the epithelial layer. In addition to being involved in immune phenomena, UC epithelial cells exhibit decreased oxidation of butyrate, downregulation of oxidative pathway regulatory genes, and overexpression of mitochondrial (mt) genes. We investigated whether these events, which translate an altered energy metabolism, are associated with an abnormal pattern of mtDNA deletions. Highly purified colonocytes were isolated from surgically resected control, involved and uninvolved inflammatory bowel disease mucosa. The frequency, type, and number of mtDNA deletions were assessed by PCR amplification, Southern blot analysis, and cloning and sequencing of amplified DNA fragments. The 4977 mtDNA deletion was less frequent in UC than control and Crohn's disease (CD) epithelium, regardless of patient age. Several other deletions were detected, but all were less common in UC than control and CD cells. The frequency, variety, and number of mtDNA deletions were invariably lower in colonocytes isolated from inflamed mucosa than in autologous cells from noninflamed mucosa. In conclusion, in the absence of inflammation, UC colonocytes exhibit an mtDNA deletion pattern similar to that of control cells, indicating a normal response to physiological levels of oxidative stress. In active inflammation, when oxidative stress increases, the frequency, variety, and number of mtDNA deletions decrease. Because comparable abnormalities are absent in active CD, the mtDNA deletion pattern of active UC suggests that colonocytes respond uniquely to inflammation-associated stress in this condition. epithelium; energy metabolism ALTHOUGH THE ETIOLOGY OF ULCERATIVE colitis (UC) is still uncertain, colonic epithelial cells (EC) have long been considered central to its pathophysiology. In addition to the restriction of the inflammatory process and associated dysplastic changes to the epithelial lining (43), there is abundant experimental evidence pointing to colonocytes as likely targets and mediators of key pathogenic events. Detection of circulating colon antibodies and cytotoxic mononuclear cells in UC patients initially suggested that colonocytes could be targets of autoimmune reactivity (6, 49). Subsequent studies demonstrated that in UC, EC express high levels of human leukocyte antigen D-related antigens (48), secrete abnormal mucin glycoconjugates (41), produce increased amounts of cytokines and chemokines (4,42,57), express costimulatory molecules (39), display autoantigens recognized exclusively by UC tissueeluted antibodies (53), and fail to mediate induction of suppressor T cells (36). Additional reports demonstrated cyclooxygenase 2 and NF-B activation (46, 51), as well as an increased rate of EC apoptosis in UC (...

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Section: Epithelium; Energy Metabolismmentioning

confidence: 99%

Section: Epithelium; Energy Metabolismmentioning

confidence: 99%

Paradoxical decrease of mitochondrial DNA deletions in epithelial cells of active ulcerative colitis patients

Fukushima¹,

Fiocchi²

2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Myopathies, neuropathies, encephalomyopathies and many other diseases have been associated with mutations in the mitochondrial DNA (mtDNA). In many of these diseases onset of clinical symptoms is late, occurring as the ratio of mutant to wildtype mtDNA passes a critical threshold depending on energy demands of the particular tissue (Graff et al, 1999;Nakada et al, 2001a). Recent studies of the effect of mtDNA mutations on disease phenotypes in a transgenic mouse model (Inoue et al, 2000;Nakada et al, 2001a;Nakada et al, 2001b;Nakada et al, 2001c;Shoubridge, 2000) suggested an important protection mechanism against the onset of disease symptoms.…”

Section: Introductionmentioning

confidence: 99%

Mitofusin-1 protein is a generally expressed mediator of mitochondrial fusion in mammalian cells

Santel

Frank

Gaume

et al. 2003

Journal of Cell Science

376

290

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Mitochondrial fusion may regulate mitochondrial morphogenesis and underlie complementation between mitochondrial genomes in mammalian cells. The nuclear encoded mitochondrial proteins Mfn1 and Mfn2 are human homologues of the only known protein mediators of mitochondrial fusion, the Drosophila Fzo GTPase and Saccharomyces cerevisiae yFzo1p. Although the Mfn1 and Mfn2 genes were broadly expressed, the two genes showed different levels of mRNA expression in different tissues. Two Mfn1 transcripts were detected at similar levels in a variety of human tissues and were dramatically elevated in heart, while Mfn2 mRNA was abundantly expressed in heart and muscle tissue but present only at low levels in many other tissues. Human Mfn1 protein localized to mitochondria and participated in a high molecular weight, detergent extractable protein complex. Forced expression of Mfn1 in cultured cells caused formation of characteristic networks of mitochondria. Introduction of a point mutation in the conserved G1 region of the predicted GTPase domain(Mfn1K88T) dramatically decreased formation of mitochondrial networks upon Mfn1 overexpression, suggesting that network formation required completion of the Mfn1 GTPase cycle. Conversely, a protein variant carrying a point mutation in the G2 motif of the Mfn1 GTPase domain acted as a dominant negative: overexpression of Mfn1T109A resulted in fragmentation of mitochondria. We propose that Mfn1T109A interferes with fusion activity of endogenous Mfn1 protein, possibly by binding necessary cofactors,so to allow unopposed mitochondrial fission. Thus, Mfn1 appears to be a key player in mediating mitochondrial fusion and morphology in mammalian cells.

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“…Mutations of mtDNA cause several genetic syndromes with deficient oxidative phosphorylation and have also been implicated in common age-associated disorders, e.g., heart failure, diabetes mellitus, and neurodegeneration (3)(4)(5). The mtDNA mutation disorders are extremely pleiotropic, and affected patients may have symptoms from almost any organ with varying ages of onset (6).…”

mentioning

confidence: 99%

Genetic modification of survival in tissue-specific knockout mice with mitochondrial cardiomyopathy

Wang

Wilhelmsson

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

174

118

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We recently described a mouse model that reproduces important pathophysiological features of mitochondrial DNA (mtDNA) mutation diseases. The gene for mouse mitochondrial transcription factor A, Tfam (also called mtTFA), a nucleus-encoded key regulator of mtDNA expression, was targeted with loxP sites (Tfam loxP ) and disrupted in vivo by transgenic expression of cre-recombinase from the muscle creatinine kinase (Ckmm) promoter. This promoter is active from embryonic day 13, and the knockouts had normal respiratory chain function in the heart at birth and developed mitochondrial cardiomyopathy postnatally. In this paper, we describe a heart-knockout strain obtained by mating Tfam loxP mice to animals expressing cre-recombinase from the ␣-myosin heavy chain (Myhca) promoter. This promoter is active from embryonic day 8, and the knockouts had onset of mitochondrial cardiomyopathy during embryogenesis. The age of onset of cardiac respiratory chain dysfunction can thus be controlled by temporal regulation of cre-recombinase expression. Further characterization demonstrated that Ϸ75% of the knockouts died in the neonatal period, whereas, surprisingly, Ϸ25% survived for several months before dying from dilated cardiomyopathy with atrioventricular heart conduction blocks. Modifying gene(s) affect the life span of the knockouts, because Ϸ95% of the knockout offspring from an intercross of the longer-living knockouts survived the neonatal period. Thus, the tissue-specific knockouts we describe here not only reproduce important pathophysiological features of mitochondrial cardiomyopathy but also provide a powerful system by which to identify modifying genes of potential therapeutic value.

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Mitochondrial medicine – recent advances

Cited by 70 publications

References 105 publications

Paradoxical decrease of mitochondrial DNA deletions in epithelial cells of active ulcerative colitis patients

Paradoxical decrease of mitochondrial DNA deletions in epithelial cells of active ulcerative colitis patients

Mitofusin-1 protein is a generally expressed mediator of mitochondrial fusion in mammalian cells

Genetic modification of survival in tissue-specific knockout mice with mitochondrial cardiomyopathy

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