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Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis

BMJ 2002; 325 doi: https://doi.org/10.1136/bmj.325.7374.1202 (Published 23 November 2002) Cite this as: BMJ 2002;325:1202

Homocysteine causes mitochondrial dysfunction

It has been proposed that an impairment of mitochondrial oxidative
phosphorylation might be the cause of atherosclerosis, thromboembolism,
hypertension and other chronic diseases of the aged including
neurodegenerative diseases and cancers (1,2,3). A meta-analysis has,
however, provided evidence of causality between elevated levels of
homocysteine and ischaemic heart disease, deep vein thrombosis and stroke
(4). Homocysteine, whose elevated levels may be restored towards normality
by folate supplements, has also been implicated in the pathogenesis of
Parkinson’s and Alzheimer’s diseases (5,6). Elevated levels of
homocysteine have also been implicated in the pathogenesis of cancers. The
two hypotheses can be reconciled because homocysteine appears to exert its
actions by altering mitochondrial gene expression, function and structure
(7-11).

Homocysteine may cause mitochondrial dysfunction and even apoptosis.
The homocysteine thiolactonyl derivative, thioretinaco ozonide, is
believed to function as an electron acceptor in oxygen metabolism and as
the binding site for adenosine triphosphate (ATP) synthesis by
mitochondria, preventing damage by free radical oxidants in resting cells.
During cell division, methionine is converted to homocysteine thiolactone,
converting thioretinaco to thioco, increasing free radical oxidants, and
oxidizing cellular glutathione and ascorbate. During cell division,
methionine is converted to homocysteine thiolactone, converting
thioretinaco to thioco, increasing free radical oxidants, and oxidizing
cellular glutathione and ascorbate. The free base of homocysteine
thiolactone produces keratinization, squamous metaplasia, dysplasia, and
carcinogenesis in normal mouse tissues. The efficiency of homocysteine
thiolactone metabolism declines with aging, explaining decreased formation
of adenosyl methionine in aging and suggesting loss of thioretinaco
ozonide from membranes of aging cells. The effects of aging on enzyme
activity, connective tissues, lipid synthesis, auto-immune diseases,
atherogenesis and carcinogenesis are related to these changes in
homocysteine metabolism.

Homocysteine acts with synergistically with H2O2 to exert some of its
noxious effects (7) and may modulate the cytotoxic effects of tumor
necrosis factor (TNF) (12,13,14). Cytokines such as TNF alpha may exert
their cytotoxic effects by opening the permeability transition pore on the
miotochondrial membrane thus uncoupling oxidative phosphorylation by
dissipating the protonmotive force upon which ATP resynthesis depends. The
beneficial effects of folic acid supplements in patients whose
homocysteine levels are elevated can, therefore, be expected to be
limited in those patients who have other causes of an impairment of
oxidative phosphorylation.

1. Hypertension: product of mitochondrial dysfunction?
Richard G Fiddian-Green
bmj.com/cgi/eletters/325/7370/917#26634, 31 Oct 2002

2. Unreversed ATP hydrolysis: the initiating endothelial event? Richard G
Fiddian-Green bmj.com/cgi/eletters/325/7369/887#26445, 22 Oct 2002

3. Iatrogenic diseases with a common cause? Richard G Fiddian-Green
bmj.com/cgi/eletters/325/7370/913#26512, 25 Oct 2002

4. Homocysteine and cardiovascular disease: evidence on causality from a
meta-analysis
David S Wald, Malcolm Law, and Joan K Morris
BMJ 2002; 325: 1202-1206.

5. Duan W, Ladenheim B, Cutler RG, Kruman II, Cadet JL, Mattson MP.
Dietary folate deficiency and elevated homocysteine levels endanger
dopaminergic neurons in models of Parkinson's disease.
J Neurochem. 2002 Jan;80(1):101-10

6. Kruman II, Culmsee C, Chan SL, Kruman Y, Guo Z, Penix L, Mattson MP.
Homocysteine elicits a DNA damage response in neurons that promotes
apoptosis and hypersensitivity to excitotoxicity.
J Neurosci. 2000 Sep 15;20(18):6920-6.

7. Austin RC, Sood SK, Dorward AM, Singh G, Shaughnessy SG, Pamidi S,
Outinen PA, Weitz JI. Homocysteine-dependent alterations in mitochondrial
gene expression, function and structure. Homocysteine and H2O2 act
synergistically to enhance mitochondrial damage.
J Biol Chem. 1998 Nov 13;273(46):30808-17

8. Mercie P, Garnier O, Lascoste L, Renard M, Closse C, Durrieu F, Marit
G, Boisseau RM, Belloc F. Homocysteine-thiolactone induces caspase-
independent vascular endothelial cell death with apoptotic features.
Apoptosis. 2000 Nov;5(5):403-11.

9. Olszewski AJ, McCully KS. Homocysteine metabolism and the oxidative
modification of proteins and lipids.
Free Radic Biol Med. 1993 Jun;14(6):683-93. Review.

10. McCully KS. Chemical pathology of homocysteine. III. Cellular function
and aging.
Ann Clin Lab Sci. 1994 Mar-Apr;24(2):134-52. Review

11. McCully KS. Chemical pathology of homocysteine. II. Carcinogenesis and
homocysteine thiolactone metabolism.
Ann Clin Lab Sci. 1994 Jan-Feb;24(1):27-59. Review.

12. .Ratter F, Gassner C, Shatrov V, Lehmann V. Modulation of tumor
necrosis factor-alpha-mediated cytotoxicity by changes of the cellular
methylation state: mechanism and in vivo relevance.
Int Immunol. 1999 Apr;11(4):519-27

13. Lassus P, Opitz-Araya X, Lazebnik Y. Requirement for caspase-2 in
stress-induced apoptosis before mitochondrial permeabilization. Science.
2002 Aug 23;297(5585):1352-4.

14. Reid RA, Moyle J, Mitchell P. Synthesis of adenosine triphosphate by a
protonmotive force in rat liver mitochondria. Nature. 1966 Oct
15;212(59):257-8

Competing interests:  
None declared

Competing interests: No competing interests

03 December 2002
Richard G Fiddian-Green
None
Formerly Professor and Chair General Surgery Univeristy of Massachusetts.
None