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Нарушения психики, митохондриальная дисфункция и соматотипы
Э. Гарднер
Каролинский университет, Стокгольм, Швеция
Psychiatric disorders, mitochondrial dysfunction, and somatotypes
Ann Gardner
Department of Clinical Neuroscience, Division of Psychiatry, Karolinska Institutet, Stockholm, Sweden
Приведены данные литературы, которые могут служить основанием для гипотезы о влиянии особенностей индивидуальных ми-тохондриальных изменений на патогенез психических нарушений и о возможной связи особенностей таких влияний с представлениями о соматотипах, высказанными в классических трудах Кречмера и Шелдона. Рассмотрены следующие группы фактов:
1. В работах Кречмера высказана гипотеза о наличии корреляции между типами телосложения и психологическими характеристиками у пациентов. Им описаны три основных соматотипа: атлетическое телосложение с хорошо развитой мышечной тканью, астеническое (дистрофическое) телосложение и пикническое — с чрезмерным развитием жировой ткани. Кречмер предположил, что существует корреляция между этими соматотипами и психиатрическими склонностями: атлетики и астеники склонны к шизофрении значительно больше, чем к маниакально-депрессивному синдрому, в то время как у лиц с пикническим телосложением наблюдалась диаметрально противоположная картина.
2. Далее автором проводится сопоставление теории Кречмера с гипотезой Шелдона о корреляциях между поведением и сома-тотипами, определяемыми относительным превалированием онтогенетического влияния наружного, среднего или внутреннего зародышевого листков (соответственно эктодермальный, мезодермальный и энтодермальный соматотипы).
3. Показано, что транскрипционные факторы, оказывающие влияние на метаболизм в митохондриях, могут повлиять на органогенез и что недостаток витамина D в эмбриогенезе влияет на экспрессию более 100 генов, участвующих в метаболизме. Обнаружено, что нарушение функций митохондрий из-за генетических или эпигенетических факторов во время эмбриогенеза связано с различными психическими расстройствами.
4. Психиатрические симптомы были описаны у пациентов с митохондриальными заболеваниями, они входят в комплекс клинических проявлений этой патологии. Описания указанных корреляций проводились в несколько этапов, при этом выяснялись закономерности между наличием определенных митохондриальных дисфункций и психиатрическими нарушениями у пациентов.
5. Приведены доказательства митохондриальных дисфункций при различных расстройствах психики.
6. Разработана классификация систем, включающая описание типа телосложения человека и его корреляции с шизофренией и биполярным расстройством. Показано, что преимущественное развитие у человека определенных типов ткани (у одной группы людей — жировой, у другой — мышечной) связано с метаболическими изменениями клеток этих тканей и оказывает влияние на формирование специфического соматотипа.
Ткким образом, совокупность представленных данных позволяет предположить, что индивидуальная вариабельность соматоти-пов и предрасположенность к различным, в первую очередь психическим, расстройствам в своей основе может иметь в том числе и митохондриальный генез.
Ключевые слова: нарушения психики, митохондриальная дисфункция, соматотипы.
The present article reviews the literature that can be the basis of the hypothesis of the influence of mitochondrial alterations on the pathogenesis of mental disorders and the possible connection between the ideas of somatotype, expressed in the classical works of Kretschmer and Sheldon. The article is based on the following chain of observations:
1. Kretschmer hypothesized the existence of correlations between body types and psychological characteristics of patients. He described three main somatotypes: athletic (with well-developed muscle tissue), asthenic (dystrophic) and pyknic (the excessive development of adipose tissue). Kretschmer suggested that there is a correlation between somatotype and psychiatric tendencies: athletics and asthenics are prone to schizophrenia much more than the manic-depressive syndrome, whereas patients with pyknic features are prone to a diametrically opposite picture.
2. The author compares the theories of Kretschmer and Sheldon and the suggestion of an ontogenetic influence on the outer, middle or inner embryonic layers (the ectoderm, mesoderm, and endoderm, respectively) with a recent report on the influence of a transcription factor affecting the mitochondrial metabolism during organogenesis. Also, vitamin D deficiency during embryogenesis has been reported to influence the adult expression of genes involved in mitochondrial metabolism.
3. Various psychiatric symptoms have been reported to be more prevalent in patients with mitochondrial disease. Psychiatric symptoms are included among the clinical manifestations of such diseases. In cases of various mental disorders, mitochondrial disease and/or dysfunction have been described. Many of the reported abnormalities in psychiatric disorders converge to impair mitochondrial function.
Thus, it can be suggested that an individual variability of somatotypes and a predisposition to a variety of disorders (including mental) may have a mitochondrial genesis in the basis.
Key words: Psychiatric disorders, mitochondrial dysfunction, somatotypes.
© Ann Gardner, 2012
Ros Vestn PerinatalPediat 2012; 4 (2):70-75
Адрес для корреспонденции: Ann Gardner — Department of Clinical Neuroscience, Division of Psychiatry, Karolinska Institutet, Stockholm, Sweden agtorndal@odenhall.se
INTRODUCTION
Mitochondria are the metabolic control cell organelles in which oxidative phosphorylation producing the bulk of cellular energy, adenosine triphosphate (ATP),
takes place. ATP production is necessary for the regulation of embryogenesis and the maintenance of cell functions during life. Mitochondrial disease can cause dysmor-phias [1—3] and many neurological, psychiatric, and other disorders. In this article, the three topics of the reported overlap between mitochondrial disease and psychiatric disorders, between psychiatric disorders and mitochondrial dysfunction, and hypothetical links between constitutional body types (somatotypes) described foremost in the pre-pharmacologial era in psychiatric disorders and the growth of the germinal epithelia formed during embryogenesis, will be shortly presented.
Mitochondrial disease and psychiatric disorders
Psychiatric symptoms have been described in patients with mitochondrial disease and are included among the clinical manifestations of the disease [4]. Although primary genetic mitochondrial disorders are relatively rare as well as underdiagnosed, three studies of psychiatric symptoms in groups of such patients have hitherto been reported.
In the first study from the US, an adult patient population of 36 patients with the presence of major and minor criteria of mitochondrial disease, were interviewed with the use of psychiatric tools. Lifetime major depressive disorder was reported by 54%, current major depressive disorder by 19%, and lifetime bipolar disorder by 17% [5]. These prevalences are high above those found in the general population. In the second study from Hungary, the results of several psychiatric tools and a structured clinical assessment in 19 adults with known mitochondrial mutations of whom six patients were free of somatic symptoms, were compared with the results of 10 adults with hereditary sensory neuropathy. No correlation between somatic and psychiatric symptoms was found in either group. The results indicated a lifetime prevalence of psychiatric diagnoses of 47% in the subjects with mitochondrial mutations, and of 30% in the subjects with sensory neuropathy. Personality disorders were indicated in 42% of the subjects with mi-tochondrial mutations and were not found in any subject with sensory neuropathy [6]. In the third study, 24 Italian adult subjects with mitochondrial disease were studied with a neuropsychiatric interview. Major depressive episode criteria were met in 58% of the subjects, and anxiety disorders criteria in 46%. These prevalences are considerably higher than those in the Italian population. Psychiatric comorbid-ity did not seem to be related to the severity or to the progression of the mitochondrial disease. The results indicate a liability for all "common" psychiatric disorders rather than for any specific mental illness in mitochondrial disease [7].
The authors of the third study commented that the possibility of mitochondrial disease should be considered in patients with psychiatric disorders especially if other major features of mitochondrial disease are present such as short stature, ptosis, ophthalmoparesis, myopathy, isolated muscle pain, dysphagia, neuropathy, ataxia, parkin-sonism, epilepsy, diabetes, and hypogonadism [7].
Although children with mitochondrial disease may be small and thin, tall subjects with progressive obesity have also been described [8]. Short stature has been reported in a third of 130 adults with mitochondrial disease [9]. Thus, there is no somatotype or physical features that distinguish patients with mitochondrial disease.
Psychiatric disorders and mitochondrial dysfunction
The relationship between depression and mitochon-drial dysfunction has been explored in several studies. Results indicating a mitochondrial involvement in postmortem brain from subjects with probable or diagnosed major depression have revealed alterations of translational products linked to mitochondrial function in the frontal, prefrontal and tertiary visual cortices, alterations of four mitochondrial-located proteins in the anterior cingulate cortex, decreased gene expression for six of 13 mtDNA-encoded transcripts in frontal cortex tissue, and of nuclear DNA-encoded mitochondrial mRNA and proteins in the cerebellum, and low levels of a nuclear DNA-encoded mi-tochondrial protein and functional activity in the prefron-tal cortex (reviewed in [10]).
Decreases of respiratory chain enzyme ratios and ATP production rates, and an increased prevalence of small deletions of the mtDNA have been reported in skeletal muscle biopsies from patients with a lifetime diagnosis of major unipolar depression with concomitant somatic symptoms. It cannot be excluded that the origin of the small deletions was the result of an inflammatory process rather than primary mitochondrial disease since breaks in the mtDNA have been reported at pro-inflammatory cytokine exposure [10, 11].
The association between mitochondrial function and bipolar(manic-depressive) disorder has been explored in many studies. The authors of a perspective paper on the topic concluded that "accumulating evidence from microarray studies, biochemical studies, neuroimaging, and postmortem brain studies all support the role of mitochondrial dysfunction in the pathophysiology of bipolar disorder. We propose that although bipolar disorder is not a classic mitochondrial disease, subtle deficits in mitochondrial function likely play an important role in various facets of bipolar disorder" [12]. In studies published thereafter, mitochondrial alterations were reported in postmortem prefrontal cortex from all patients with bipolar disorder [13], and abnormalities of mitochondrial structure in postmortem prefrontal cortex, fibroblasts and lymphocytes [14].
The involvement of other tissues than the brain such as lymphocytes has been reported also in schizophrenia [15]. Alterations of muscle cells, another tissue of meso-dermal embryogenic origin, have been reported in depressive disorders [11] and schizophrenia [16]. The observation in schizophrenia was interpreted to suggest that schizophrenia is in fact a systemic disorder. Cases of schizophrenia have been reported in mitochondrial disease [4]. Central obesity, an increase of visceral fat distribution in
the presence of normal body weight, has been reported even in drug-naive patients with schizophrenia as well as in patients with depression [17]. In the largest family study of schizophrenia and bipolar disorder ever undertaken, the results indicated that first-degree relatives of probands with schizophrenia or bipolar disorder have an increased risk of both disorders, and that this is mainly due to genetic factors [18]. In a Lancet Editorial commenting upon the findings, it was suggested that the dichotomization into two disorders originating more than 100 years ago by the German psychiatrist Emil Kraepelin (1856—1926), and reified in the currently used classifications of psychiatric disorders assuming two discrete, natural disease entities with distinct pathogenesis, should be reconsidered [19].
The authors of a recent review article concluded that many of the upstream abnormalities in psychiatric disorders converge to impair mitochondrial function, resulting in abnormalities in synaptic plasticity and long-term cellular resilience [20].
Epigenetic alterations affecting mitochondrial function
Deficiency of vitamin D (a hormone regulating the expression of more than 100 genes) during embryogenesis has been suggested to be a causative factor in autism [21] and schizophrenia [22, 23]. Offspring of vitamin D-deficient rat mothers, restored to a normal diet at birth, have persistent brain alterations during adulthood including larger lateral ventricles. In a study investigating the molecular pathways mediating these changes, 74 dysregulated gene transcripts were identified in brains of offspring at 10 weeks (rats become sexually mature at six weeks), of which the majority were downregulated. Of these 74 altered transcript molecules, 54 were found to affect mitochondria, cytoskeletal maintenance, and synapses. The majority were derived from genes affecting mitochondria, some directly involved in ATP production. Mitochondria are thus the subcellular compartment affected the most by alterations of the gene expression in adulthood after this type of insult during embryogenesis. The authors end their report "We speculate that these changes could lay the foundation (or 'first hit') for a range of adult disorders. Combined with specific susceptibility genes, and additional specific postnatal exposures ('second hits' suchas infection, substance abuse, stress, etc.), vitamin D deficiency may contribute to a previously unrecognized range of adverse health out-comes"[24].
Embryogenesis and mitochondrial function, and somato-types in personality and psychiatric disorders
The mitochondrial transcription termination factor (MTERF) family comprises a group of evolutionary conserved nuclear DNA-derived proteins consisting of four subfamilies [25]. MTERF1 has been found to bind to a 28-base pair region within the mitochondrial DNA (mtDNA) in the tRNALeu(UUR) gene at a position adjacent and downstreams of the 16S rRNA gene. MTERF2 binds to the heavy strand promoter (HSP) region of the mtDNA. MTERF3 functions as a negative regulator
of mammalian mtDNA transcription. A component of the MTERF4 subfamily, Mterfid2, has been suggested to play a central role in the complex coordination of the regulation of mitochondrial metabolism. Mterfid2 is dynamically expressed during embryogeneis in mice embryos. The earliest expression at determination at several embryogenic stages was observed in the brain, lateral phase mesoderm (forming skeletal muscle, the skeleton, the dermis of skin, connective tissue, the urogenital system, the heart, the lymph cells, the kidney, and the spleen) and heart. At the second determined stage, there was expression in the forebrain, ear pinna, trigeminal areas, limb buds, lateral phase me-soderm and heart. At the third stage, expression was abundant in forebrain, midbrain and limb buds, and weak signs were observed in the otic vesicle and the neural tube. At the fourth stage there was high expression in the brain, and expression in the spinal cord, dorsal root ganglia, olfactory epitelium and tongue. At the fifth stage there was high expression in the forebrain, midbrain, spinal cord, tongue, liver and kidney. Since Mterfid2 was expressed at the later stages in the main organs and other supportive tissues, its multiple roles in organogenesis was supported. The expression may affect cognition [25]. The mtDNA region binding to MTERF1 (nucleotides 3229—3256) contains two polymorphic sites (3250 and 3254) which, though noncoding, both are listed as disease-associated/causing mutations, as well as five disease-causing mutations [26]. It is unknown if MTERF binding may be affected by such variations in the mtDNA.
The American psychologist William Herbert Sheldon Jr (1898—1977) presented correlations between behavior and somatotypes after having examined the relation between body structure and personality, and developed a version of somatotypology by classifying people with endo-morphic, mesomorphic, and ectomorphic character components. According to Sheldon, during the development of embryo, one of the three germinal tissues, the innermost endoderm layer (forming the stomach, the colon, the liver, the pancreas, the urinary bladder, the lining of the urethra, the epithelial parts of trachea, the lungs, the pharynx, the thyroid, the parathyroid, and the intestines), the meso-derm layer (see above), and the ectoderm layer (forming the central nervous system, the lens of the eye, the ganglia and nerves, pigment cells, head connective tissues, the epidermis, hair, and mammary glands) become deterministic. Sheldon did not draw a definitive line between these three somatotypes and claimed that every person could have some level of these [27, 28].
The German psychiatrist Ernst Kretschmer (1888— 1964) developed a classification system based on three constitutional body types associated with psychopa-thology in their more extreme forms [29]. According to Kretschmer, the asthenic/leptosomic (thin, small, weak) type (Figure 1) was associated with narrow shoulders and body, long arms and legs, thin and long bones in hands and feet, aging ahead of time, and to be intro-
verted and timid and outsiders from the society. This was seen as a milder form of the negative symptoms exhibited by withdrawn schizophrenics. The ectomorphic type as described by Sheldon was almost in accordance with the leptosomic type of Kretschmer. Sheldon considered this type as due to a preferential development of the embryo of the ectoderm layer: the skin, brain and nervous system.
Figure 1. The asthenic body type [29].
The pyknic (stocky, fat) type (Figure 2) is extraverted, friendly, cheery, interpersonally dependent, gregarious, comfortable and sincere, do not have a complicated nature. The obese are predisposed toward manic-depressive (bipolar) illness. The endomorphic type of Sheldon was almost in accordance with the pyknic type of Kretschmer. The endomorphic body structure is related to the development of internal organs involving digestion, respiration, blood circulation, and fat structure.
The athletic (muscular, large—boned) type (Figure 3) is associated with strong development of the skeleton and muscle structure, broad shoulders, muscled waist, body length above average, and the development of fattening in females. The athletic type is slow, cheerful, or aggressive. The mesomorphic type as described by Sheldon has a well developed skeleton and muscle system and broad shoul-
Figure 2. The pyknic body type [29].
Figure 3. The athletic body type [29].
ders, and aggressive, bold and robust personality features.
Kretschmer noticed that very few patients with schizophrenia had the pyknic body type and that manic-depressive patients seldom had the asthenic type. When manic-depressives did not present the pure pyknic type as in 14 cases (his figures are presented in the table below; Table 5 in [29]), in five cases there was a mixture with athletic features and in three cases with asthenic features.
In a book review of the third German 1922 issue of Kretschmer's book describing the classification system, the reviewer ends "We feel that there is however a great deal of truth in his theory and he has opened up a study which will surely prove a fascinating and important field
Table. Correspondence of somatotypes and psychiatric disorders [29].
Body types Manic-depressive Schizophrenia
Asthenic 4 81
Athletic 3 31
Asthenic-athletic, mixed 2 11
Pyknic 58 2
Pyknic, complex forms 14 3
Dysplastic 0 34
Unidentified types 4 13
Total number of patients 85 175
of research" [30]. Interest in the association of somatotypes with psychopathologies faded in the 1950s [31]. The psychopharmacological agents that were introduced in the 1950s, and which oftentimes cause weight gain and sometimes prominent alterations of the physical appearance, make distinctions of premorbid somatotypes less ascertainable in many medicated patients. An association between the asthenic somatotype and panic and/or agoraphobia has been described foremost in younger patients, and in those with joint hypermobility. The authors concluded that the results provide some clinical support for examining somatotype in psychiatric patients [31]. In a 2009 study, the authors write that studies on somatology and morphometry have been obtaining increasing interest in the recent psychiatric literature. No significant relationships were found between somatotypes in 34 schizophrenia cases, all taking antipsychotic medications, compared to 32 non-clinical controls. However, at controlling for en-domorphism and ectomorphism in the patients, there was a significant correlation between psychopathology scores with mesomorphism (similar to the athletic type described by Kretschmer) [32].
In summary, correlations between body types/somato-types and psychologic characteristics have a long history in mankind and did not begin with the observations by the American psychologist William Herbert Sheldon and
the German psychiatrist Ernst Kretschmer in the early part of the last century. Classification systems as that by Kretschmer including the description of a body type linked to schizophrenia, and another to bipolar disorder, have become difficult to make since the advent of psy-chopharmacological agents affecting fat distribution and body mass. Recent research indicate that underdevel-opment of some tissues, and preferential development of others, are likely to be due to metabolic cell alterations in these tissues, and might give rise to specific somato-types. We now know that genetic transcription factors affecting the metabolism of the mitochondria producing cellular energy may impact on the organogenesis in the embryonic stage, and that a lack of vitamin D during embryogenesis affects the adult expression of genes involved in mitochondrial energy production. Recent studies link deficiencies in mitochondrial function and energy production with various psychiatric disorders. Alterations of mitochondrial function due to genetic or epigenetic changes during embryogenesis could lay the foundation for a range of adult psychiatric disorders when combined with susceptibility genes, and additional specific post-natal exposures. Thus, novel interpretations may shed light on the observations prompting the classification systems developed by Sheldon and Kretschmer.
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Поступила 04.07.12
