Mitochondrial involvement in psychiatric disorders

Figures & data

Table

^31P-MRS	phosphorus-31 magnetic resonance spectroscopy
ASR	agonal stress rating
ATP	adenosine triphosphate
BPD	bipolar disorder
C	controls
CGLN	cerebellar granular cell layer
CoQ	coenzyme Q
CPZ	chlorpromazine
Ct	cycle threshold
MT-CO1	cytochrome c oxidase I
MT-CO2	cytochrome c oxidase II
MT-CO3	cytochrome c oxidase III
CPEO	chronic progressive external ophthalmoplegia
MT-CYB	cytochrome b
MT-CYC	cytochrome c
DISC1	disrupted in schizophrenia 1
D-loop	displacement loop
DLPFC	dorsolateral prefrontal cortex
FDG	fluoro-deoxy-glucose
LHON	Leber hereditary optic neuropathy
MDD	major depressive disorder
MELAS	mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes
MNGIE	mitochondrial neurogastrointestinal encephalomyopathy
[1H]-MRS	1H-magnetic resonance spectroscopic imaging
MtDNA	mitochondrial DNA
MT-ATP6	ATP synthase 6
MT-ATP8	ATP synthase 8
MT-ND1	nicotinamide adenine dehydrogenase 1
MT-ND2	nicotinamide adenine dehydrogenase 2
MT-ND3	nicotinamide adenine dehydrogenase 3
MT-ND4	nicotinamide adenine dehydrogenase 4
MT-ND4L	nicotinamide adenine dehydrogenase 4L
MT-ND5	nicotinamide adenine dehydrogenase 5
MT-ND6	nicotinamide adenine dehydrogenase 6
NAA	N-acetylaspartate
NADH	nicotinamide adenine dinucleotide
OXPHOS	oxidative phosphorylation
PMI	post-mortem interval
POLG	polymerase DNA-directed gamma
Q-PCR	quantitative polymerase chain reaction
SNP	single nucleotide polymorphism
SZ	schizophrenia

Figure 1.  Diagram adapted from Lee et al. 106 showing five complexes involved in oxidative phosphorylation. We found decreased expression in brain for key mitochondrial DNA-encoded transcripts in neuropsychiatric disorders as shown in Table II.

Table I.  Demographics of four groups of subjects from which DLPFC was obtained. All subjects had a rapid death and absence of prolonged hypoxia prior to death.

		pH		Age (yrs)		agonal stress rating		Gender
	n	Ave	SD	Ave	SD	Ave	SD	Male/female
BPD	12	6.87	0.16	50	17	−0.2	0.92	9/3
MDD	15	6.96^a	0.19	51	15	0.3^a	0.81	10/4
SZ	14	6.87	0.24	45^a	9	−0.3	0.82	11/2
C	37	6.81	0.19	53	13	−0.3	1.05	29/6

^aP<0.05 compared to controls.

ASR = agonal stress rating; BPD = bipolar disorder; C = Control; DLPFC = dorsolateral prefrontal cortex; MDD = major depressive disorder; SD = standard deviation; SZ = schizophrenia.

Table II.  Gene expression results of 13 mitochondrial genes and D-loop. The t test and ANCOVA values are shown.

	t test						ANCOVA
	P value			Fold			P value			Fold
	BPD	MDD	SZ	BPD	MDD	SZ	BPD	MDD	SZ	BPD	MD	SZ
D-loop	0.50	0.051	0.002^a	0.89	0.83	0.72	0.46	0.114	0.009^a	0.92	0.81	0.71
MT-ATP6	0.88	0.013^a	0.003^a	0.97	0.76	0.72	0.81	0.027^a	0.010^a	1.03	0.74	0.72
MT-ATP8	0.79	0.034^a	0.002^a	0.96	0.72	0.73	0.99	0.015^a	0.018^a	1.00	0.70	0.72
MT-CO1	0.94	0.060	0.004^a	1.01	0.77	0.75	0.66	0.039^a	0.118	1.06	0.72	0.79
MT-CO2	0.84	0.078	0.004^a	0.96	0.79	0.75	0.94	0.091	0.093	1.01	0.77	0.78
MT-CO3	0.64	0.150	0.006^a	0.91	0.79	0.70	0.70	0.124	0.035^a	0.94	0.76	0.70
MT-CYB	0.72	0.074	0.003^a	0.94	0.82	0.70	0.74	0.197	0.016^a	0.95	0.82	0.69
MT-ND1	0.96	0.003^a	0.001^a	1.01	0.74	0.72	0.55	0.014^a	0.027^a	1.07	0.73	0.77
MT-ND2	0.89	0.096	0.015^a	0.98	0.84	0.74	0.98	0.174	0.011^a	1.00	0.82	0.69
MT-ND3	0.70	0.220	0.016^a	0.92	0.84	0.69	0.64	0.297	0.016^a	0.92	0.82	0.64
MT-ND4	0.88	0.052	0.010^a	0.97	0.85	0.75	0.89	0.194	0.012^a	0.98	0.83	0.69
MT-ND4L	0.90	0.011^a	0.009^a	1.02	0.75	0.79	0.55	0.008^a	0.137	1.07	0.70	0.83
MT-ND5	0.75	0.048^a	0.006^a	1.05	0.84	0.78	0.38	0.082	0.028^a	1.10	0.81	0.78
MT-ND6	0.90	0.031^a	0.002^a	1.02	0.77	0.78	0.64	0.004^a	0.031^a	1.05	0.68	0.77

^aP value (P<0.05) significant after matching controls and psychiatric subjects for pH, ASR, and age: “Abbreviations: D-Loop – displacement loop; BPD – bipolar disorder; MDD – major depressive disorder; SZ – schizophrenia; ASR – agonal stress rating”.

Figure 2.  The mitochondrial common deletion is increased in psychiatric disorders. The individual subjects are plotted by age and common deletion (x-axis ratio of 350/5000 bp). Subjects with BPD died at a younger age in this study; there was a significant increase in common deletion after age adjustment. The blue circle indicates the 95% confidence limits around the control subjects. The increase in the common deletion for nine psychiatric subjects is shown outside of the blue circle. Group abbreviations are shown in Table I.

Figure 3.  Genotyping for large common deletion. Subjects were genotyped in duplicate at two concentrations. Arrows indicate presence of deletion relative to 5000 bp upper non-deleted band. Group abbreviations are shown in Table I.

Table III.  Mitochondrial common deletion (ratio of 350 bp/5000 bp) is increased in BPD. PCR amplification around the deleted fragment (350 bp) and the non-deleted fragment (5000 bp) was measured in the same PCR reaction and Agilent gel lane (see Figure 3). This assay was linear in the range of 10–20 ng of DNA (r=0.98), and duplicate values were averaged for each sample.

Group	n^a	Fold change compared to controls	P value
Controls	37
BPD	12	2.12	0.006
MDD	15	1.82	0.077
SZ	14	1.59	0.17

^aThe ANCOVA factors included diagnosis, gender, pH, and age. The common deletion ratio was increased significantly 1.84-fold across all psychiatric disorders compared to controls.

Fold change was calculated as 2^{(AVERAGE (Control Group)–AVERAGE (Experimental Group)}. Group abbreviations are shown in Table I.

Lee HC, Li SH, Lin JC, Wu CC, Yeh DC, Wei YH. Somatic mutations in the D-loop and decrease in the copy number of mitochondrial DNA in human hepatocellular carcinoma. Mutat Res. 2004; 547: 71–8

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