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Mitochondrial DNA mutations in diabetic heart
DiabetesResearchand Clinical Practice31 Suppl.(1996)S123-S126
Mitochondrial
DNA mutations in diabetic heart Nobuakira Takeda
Aofo641-2,KQsushika-ku, T&p Department of Internal Medicine, Aoto Hospital, The Jikei University, School of Medicine, Japan
125,
Abstract
Mutations of mitochondrial DNA have been found in cardiomyopathic and diabetic patients as well as mitochondrial myopathic patients. Mitochondrial DNA mutations are maternally transmitted. It has also been reported that these mutations can be acquired under the influence of free radicals. This article is a mini-review about mutations of mitochondrial DNA related to the diabetic heart. Keywords: Diabetes mellitus; Mitochondrial DNA; Cardiomyopathy; Free radicals
1. Introduction
2.324~Point mutation
Gene abnormalities in diabetes mellitus have recently been reported, including abnormalities of the insulin gene, insulin receptor gene, glucokinase
gene and mitochondrial genes. This article is a mini-review about mutations of mitochondrial DNA related to the diabetic heart. The mitochondrion has its own DNA, which is a double-stranded circular structure, comprising 16 569 base pairs [l]. It encodes 13 proteins, 22 tRNAs, and 2 rRNAs. Mutations of mitochondrial DNA are maternally inherited [2,3] and can exist in multiple organs. Mitochondrial DNA mutations in cardiomyopathy were first reported by Ozawa et al. in 1990 [4], and mutations in mitochondrial myopathy were reported by Goto et al. in 1990
A point mutation of adenine (A) to guanine (G) at position 3243 of mitochondrial DNA within tRNALeu(“UR) was first found in patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) and its presence was subsequently confirmed in more than 90% of MELAS cases [5,6]. Recently, this point mutation has also been found in some diabetic patients with sensory deafness.Two pedigrees of maternally transmitted diabetes mellitus and deafnessassociated with A-to-G transition at position 3243 of mitochondrial DNA were reported in 1992 [7,8]. One of the pedigreesincluded casesassociated with mitral valve prolapse [7] and the other cases associated with cardiomyopathy
c51.
L-0
0168-8227/96/%15.00 CQ 1996 Elsevier Ireland Ltd. All rights reserved PII SO168-8227(96)01239-9
S124
N. Take&I
Diabetes Research and Clinical Practice 31 Suppl. (1996) S123-Sl26
Fig. 1. Echocardiograph. Left ventricular hypertrophy is remarkable.
Approximately 1% of Japanesediabetic patients possessthis 3243-point mutation [9,10]. Figure 1 shows an echocardiograph of a diabetic patient with hypertrophic cardiomyopathy, who subsequently died of heart failure, Myocardial mitochondrial DNA was examined using autopsy material, and digestion PCR with the restriction enzyme Apa I revealed two additional bands (Fig. 2). This was one of the cases which ,possessedan A-to-G point mutation at position 3243 within tRNAL’“‘“UR) of the mitochondrial DNA. Fig. 3 shows a diagrammatic representation of insulin secretion from pancreatic p-cells. It is necessaryto clarify the relationship between the mitochondrial DNA point mutation and insulin secretion. However, at the moment, it can be said that the mutation ,at position 3243 of mitochondrial DNA is a common gene abnormality in most patients with MELAS, a proportion of patients with cardiomyopathy and some diabetic patients.
C 800bp =\446 bp 354bo
0 before Apal digestion 0 after Apal difjusthn Fig. 2. A point mutation of mitochondrial DNA. Myocardial mitochondrial DNA was extracted from autopsy materials. Patient B possesseda point mutation at position 3243.
N. TakedalDiabetes
S125
Research and Clinical Practice 31 Suppl. (1996) S123-S126
Glucose Target cell
p cell (Pancreas)
GLUT2
Insulin receptor +*Insulin
ATP
P ?
... Muscle ... Fat
SU receptor
\1 K+
I Fig. 3. Hypothetical mechanism of insulin secretion.
ml MI ADR
Fig. 4. Mitochondrial DNA deletion in human autopsied myocardium which could be considered an acquired mutation. ADR, malignancy treated with adriamycin; DM, diabetes melIitus; MI, myocardial infarction. Hatched columns indicate casesshowing mitochondrial DNA deletion.
3. Other mutations
Other new mitochondrial DNA mutations have been reported. Ballinger et al. found a 10.4-kb deletion in patients with maternally transmitted diabetes associated with deafness,and part of the pedigree showed cardiomyopathy [ll]. We have reported a myocardial mitochondrial DNA deletion of 7.4 kb between the D-loop and the ATPase genes in autopsy materials from diabetic patients [12,13]. Free radicals produced in these patients might play a role in inducing these deletions (Fig. 4). However, there was no clear relationship be-
tween the presence of the myocardial mitochondrial DNA deletion and cardiac manifestations in these patients. This might have been because the amount of deleted mitochondrial DNA was insufficient to induce cardiac functional disturbance. These findings suggest that detection of mitochondrial DNA mutation might become a useful diagnostic method for cardiac disorders. References [l] Anderson, S., Bankier, A.T., Barrel], B.G. et al. (1981) Sequence and organization of the human mitochondrial genome. Nature 290,457-465. [2] Giles, R.E., Blanc, H., Cann, H.M. and Wallace, DC. (1980) Maternal inheritance of human mitochondrial DNA. Proc. Natl. Acad. Sci. USA 77,6715-6719. [3] Ozawa, T., Yoneda, M., Tanaka, M. et al. (1980) Maternal inheritance of deleted mitochondrial DNA in a family with mitochondrial myopathy. Biochem. Biophys. Res. Commun. I 54, 1240- 1247. [4] Ozawa, T., Tanaka, M., Sugiyama, S. et al. (1990) Multiple mitochondrial DNA deletions exist in cardiomyocytes of patients with hypertrophic or dilated cardiomyopathy. Biochem. Biophys. Res. Commun. 170, 830-836. [S] Goto, Y., Nonaka, I. and Horai, A. (1990) A mutation in the tRNALc”‘“UR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348,651-653. [6] Tanaka, M., Ino, H., Ohkubo, K. et al. (1991) Mitochondrial DNA mutations in mitochondrial myopathy, en-
S126
[7]
[S]
[9] [lo]
N. Takedal Diabetes Research and Clinical Practice 31 Suppl. (1996) S123-S126
cephalopathy, lactic acidosis and stroke-like episodes (MELAS). Biochim. Biophys. Acta 1097,238-240. van den Ouweland, J.M.W., Lemkes, H.H.P.J., Ruitenbeek, K. et al. (1992) Mutation in mitochondrial tRNAL’“(““sr gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness.Nature Genet. 1, 368-371. Reardon, W., Ross, R.J.M., Sweeney, M.U. et al. (1992) Diabetes mellitus associated with a pathogenic point mutation in mitochondrial DNA. Lancet 340,1376-1379. Kadowaki, T., Kadowaki, H., Mori, Y. et al. (1994) A subtype of diabetes mellitus associatedwith a mutation of mitochondrial DNA. N. Engl. J. Med. 330,962-968. Katagiri, H., Asano, T., Ishihara, H. et al. (1994) Mitochondrial diabetes mellitus: prevalence and clinical
characterization of diabetes due to mitochondrial tRNA(Leu(UUR)) gene mutation in Japanese. Diabetologia 37, 504510. [l I] Ballinger, SW., Schoffner,J.M. and Hedaya, H.V. (1992) Maternally transmitted diabetes and deafness associated with a IO.4kb mitochondrial DNA deletion. Nature Genet. I, 11-15. [I23 Takeda, N., Tanamura, A., Iwai, T. et al. (1993) Mitochondrial DNA deletion in human myocardium. Mol. Cell. Biochem. 119, 105-108. [13] Takeda, N., Tanamura, A., Iwai, T. et al. (1995) Mutations of myocardial mitochondrial DNA in diabetic patients. In: N.S. Dhalla, G.N. Pierce, V. Panagia and R.E. Beamish (Eds.), Heart Hypertrophy and Failure, Kluwer Academic Pub]., Boston, pp. 59-66.
Mitochondrial
DNA mutations in diabetic heart Nobuakira Takeda
Aofo641-2,KQsushika-ku, T&p Department of Internal Medicine, Aoto Hospital, The Jikei University, School of Medicine, Japan
125,
Abstract
Mutations of mitochondrial DNA have been found in cardiomyopathic and diabetic patients as well as mitochondrial myopathic patients. Mitochondrial DNA mutations are maternally transmitted. It has also been reported that these mutations can be acquired under the influence of free radicals. This article is a mini-review about mutations of mitochondrial DNA related to the diabetic heart. Keywords: Diabetes mellitus; Mitochondrial DNA; Cardiomyopathy; Free radicals
1. Introduction
2.324~Point mutation
Gene abnormalities in diabetes mellitus have recently been reported, including abnormalities of the insulin gene, insulin receptor gene, glucokinase
gene and mitochondrial genes. This article is a mini-review about mutations of mitochondrial DNA related to the diabetic heart. The mitochondrion has its own DNA, which is a double-stranded circular structure, comprising 16 569 base pairs [l]. It encodes 13 proteins, 22 tRNAs, and 2 rRNAs. Mutations of mitochondrial DNA are maternally inherited [2,3] and can exist in multiple organs. Mitochondrial DNA mutations in cardiomyopathy were first reported by Ozawa et al. in 1990 [4], and mutations in mitochondrial myopathy were reported by Goto et al. in 1990
A point mutation of adenine (A) to guanine (G) at position 3243 of mitochondrial DNA within tRNALeu(“UR) was first found in patients with MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) and its presence was subsequently confirmed in more than 90% of MELAS cases [5,6]. Recently, this point mutation has also been found in some diabetic patients with sensory deafness.Two pedigrees of maternally transmitted diabetes mellitus and deafnessassociated with A-to-G transition at position 3243 of mitochondrial DNA were reported in 1992 [7,8]. One of the pedigreesincluded casesassociated with mitral valve prolapse [7] and the other cases associated with cardiomyopathy
c51.
L-0
0168-8227/96/%15.00 CQ 1996 Elsevier Ireland Ltd. All rights reserved PII SO168-8227(96)01239-9
S124
N. Take&I
Diabetes Research and Clinical Practice 31 Suppl. (1996) S123-Sl26
Fig. 1. Echocardiograph. Left ventricular hypertrophy is remarkable.
Approximately 1% of Japanesediabetic patients possessthis 3243-point mutation [9,10]. Figure 1 shows an echocardiograph of a diabetic patient with hypertrophic cardiomyopathy, who subsequently died of heart failure, Myocardial mitochondrial DNA was examined using autopsy material, and digestion PCR with the restriction enzyme Apa I revealed two additional bands (Fig. 2). This was one of the cases which ,possessedan A-to-G point mutation at position 3243 within tRNAL’“‘“UR) of the mitochondrial DNA. Fig. 3 shows a diagrammatic representation of insulin secretion from pancreatic p-cells. It is necessaryto clarify the relationship between the mitochondrial DNA point mutation and insulin secretion. However, at the moment, it can be said that the mutation ,at position 3243 of mitochondrial DNA is a common gene abnormality in most patients with MELAS, a proportion of patients with cardiomyopathy and some diabetic patients.
C 800bp =\446 bp 354bo
0 before Apal digestion 0 after Apal difjusthn Fig. 2. A point mutation of mitochondrial DNA. Myocardial mitochondrial DNA was extracted from autopsy materials. Patient B possesseda point mutation at position 3243.
N. TakedalDiabetes
S125
Research and Clinical Practice 31 Suppl. (1996) S123-S126
Glucose Target cell
p cell (Pancreas)
GLUT2
Insulin receptor +*Insulin
ATP
P ?
... Muscle ... Fat
SU receptor
\1 K+
I Fig. 3. Hypothetical mechanism of insulin secretion.
ml MI ADR
Fig. 4. Mitochondrial DNA deletion in human autopsied myocardium which could be considered an acquired mutation. ADR, malignancy treated with adriamycin; DM, diabetes melIitus; MI, myocardial infarction. Hatched columns indicate casesshowing mitochondrial DNA deletion.
3. Other mutations
Other new mitochondrial DNA mutations have been reported. Ballinger et al. found a 10.4-kb deletion in patients with maternally transmitted diabetes associated with deafness,and part of the pedigree showed cardiomyopathy [ll]. We have reported a myocardial mitochondrial DNA deletion of 7.4 kb between the D-loop and the ATPase genes in autopsy materials from diabetic patients [12,13]. Free radicals produced in these patients might play a role in inducing these deletions (Fig. 4). However, there was no clear relationship be-
tween the presence of the myocardial mitochondrial DNA deletion and cardiac manifestations in these patients. This might have been because the amount of deleted mitochondrial DNA was insufficient to induce cardiac functional disturbance. These findings suggest that detection of mitochondrial DNA mutation might become a useful diagnostic method for cardiac disorders. References [l] Anderson, S., Bankier, A.T., Barrel], B.G. et al. (1981) Sequence and organization of the human mitochondrial genome. Nature 290,457-465. [2] Giles, R.E., Blanc, H., Cann, H.M. and Wallace, DC. (1980) Maternal inheritance of human mitochondrial DNA. Proc. Natl. Acad. Sci. USA 77,6715-6719. [3] Ozawa, T., Yoneda, M., Tanaka, M. et al. (1980) Maternal inheritance of deleted mitochondrial DNA in a family with mitochondrial myopathy. Biochem. Biophys. Res. Commun. I 54, 1240- 1247. [4] Ozawa, T., Tanaka, M., Sugiyama, S. et al. (1990) Multiple mitochondrial DNA deletions exist in cardiomyocytes of patients with hypertrophic or dilated cardiomyopathy. Biochem. Biophys. Res. Commun. 170, 830-836. [S] Goto, Y., Nonaka, I. and Horai, A. (1990) A mutation in the tRNALc”‘“UR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature 348,651-653. [6] Tanaka, M., Ino, H., Ohkubo, K. et al. (1991) Mitochondrial DNA mutations in mitochondrial myopathy, en-
S126
[7]
[S]
[9] [lo]
N. Takedal Diabetes Research and Clinical Practice 31 Suppl. (1996) S123-S126
cephalopathy, lactic acidosis and stroke-like episodes (MELAS). Biochim. Biophys. Acta 1097,238-240. van den Ouweland, J.M.W., Lemkes, H.H.P.J., Ruitenbeek, K. et al. (1992) Mutation in mitochondrial tRNAL’“(““sr gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness.Nature Genet. 1, 368-371. Reardon, W., Ross, R.J.M., Sweeney, M.U. et al. (1992) Diabetes mellitus associated with a pathogenic point mutation in mitochondrial DNA. Lancet 340,1376-1379. Kadowaki, T., Kadowaki, H., Mori, Y. et al. (1994) A subtype of diabetes mellitus associatedwith a mutation of mitochondrial DNA. N. Engl. J. Med. 330,962-968. Katagiri, H., Asano, T., Ishihara, H. et al. (1994) Mitochondrial diabetes mellitus: prevalence and clinical
characterization of diabetes due to mitochondrial tRNA(Leu(UUR)) gene mutation in Japanese. Diabetologia 37, 504510. [l I] Ballinger, SW., Schoffner,J.M. and Hedaya, H.V. (1992) Maternally transmitted diabetes and deafness associated with a IO.4kb mitochondrial DNA deletion. Nature Genet. I, 11-15. [I23 Takeda, N., Tanamura, A., Iwai, T. et al. (1993) Mitochondrial DNA deletion in human myocardium. Mol. Cell. Biochem. 119, 105-108. [13] Takeda, N., Tanamura, A., Iwai, T. et al. (1995) Mutations of myocardial mitochondrial DNA in diabetic patients. In: N.S. Dhalla, G.N. Pierce, V. Panagia and R.E. Beamish (Eds.), Heart Hypertrophy and Failure, Kluwer Academic Pub]., Boston, pp. 59-66.