Table 3.
Studies reporting the results of mtDNA analyses in postmortem brain samples of patients with psychiatric diseases (PsyD).
| Study reference (PMID) |
Patient/Control characteristics | Disease (N) |
Brain region | Technique | mtDNA alteration in brain | Additional information | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| N P/C |
Age (y) in P/C |
Sex M/F |
Variant | mtDNA CN | Rearrangements | |||||
| Fries et al. 2019 (31746071) |
32/32 | 45/47 | P: 15/17 C: 19/13 |
BD (32) | Hi | qPCR | NR | Less mtDNA CN in BD P vs. C. Significant correlations between telomere length and mtDNA CN |
NR | mtDNA CN was not correlated with chronological age |
| Hjelm et al. 2019 (30869147) |
39/2 | 46 | 33/8 | SZ (12) BD (10) MDD (9) ADO (8) C (2) |
ACCtx, DLPFCtx, Hi, Pu, Cd |
Long-range PCR and NGS, exome sequencing, splice-break pipeline, qPCR, Sanger sequencing |
NR | NR | The study identified 4489 DELs: 513 with size range 7–8 kb and 127 with size of approximately 50 bp; 346 unique; 12 out of the 30 most frequent DELs were previously described. 13 high-impact DELs (read rate ≥ 5%) were present in 14 brain tissue samples of 9 subjects with psychiatric diagnoses. The group of subjects with SZ or BD had a higher DLPFCtx/ACCtx DEL ratio than the group of C, MDD or ADO subjects. The highest DEL burdens occurred in two subjects with MDD. The common DEL was neither the most frequent nor the most abundant |
Brain samples contained significantly more DELs and higher cumulative read percentages than blood samples. The 13 high-impact DELs detected in the brain were not detected in the blood. Many individual DELs had significant positive correlations with age The highest DEL burdens were observed in MDD P, at higher levels than KKS muscle |
| Bodenstein et al. 2019 (31797868) |
66/37 | Hi C: 60 BD: 59 SZ: 62 BA24 and Cb C: 71 BD: 72 SZ:69 PFCtx C: 72 BD: 65 SZ: 71 |
NA | SZ (35) BD (31) C (37) |
Hi, BA24, Cb, PFCtx | qPCR | NR | BD group had significantly higher mtDNA content for MT- ND4 and MT-ND5 in Hi tissue compared to C. Cb of patients with BD or SZ also had higher mtDNA CN than BA24 region of the same patients | No significant alteration in the accumulation of the common mtDNA DEL across the brain regions and groups | BA24 and Cb tissues came from the same patients |
| Otsuka et al. 2017 (28600518) |
20/25 | SV: 52 C: 58 |
SV:11/9 C: 19/6 |
SV (20) C (25) |
DLPFCtx | qPCR | NR | Significantly lower mtDNA CN in the DLPFC of SV compared to C (p = 0.0044) | NR | In the DLPFCtx of SV, significantly shorter telomere length was reported (p = 0.0014) |
| Rollins et al. 2018 (29594135) |
53/41 | BD: 46 SZ: 41 C: 58 |
BD: 13/13 SZ: 24/3 C: 35/6 |
BD (26) SZ (27) C (41) |
PFCtx | qPCR with SYBR green and TaqMan probes | NR | BD and SZ groups displayed a significant increase in mtDNA CN (p= 0.028 and p= 0.025, respectively) | No significant decrease in mtDNA common DEL in PFCtx of patients with SZ. Female subjects displayed 60% increase in the accumulation of the common DEL |
Complex I ELISA data indicated that the brains of SZ and BD had fewer functional mitochondria with larger amounts of mtDNA compared to controls |
| Mamdani et al. 2014 (25270547) |
30/10 | MDD: 48 BD: 52 SZ: 47 C: 46 |
MDD: 3/7 BD: 5/5 SZ: 5/5 C: 7/3 |
MDD (10) BD (10) SZ (10) C (10) |
ACCtx, Amg, Cd, DLPFCtx, Hi, Ac, OFCtx, Pu, SN, and Th | qPCR, Sanger sequencing | NR | NR | Common DELs in SZ were significantly decreased, mostly in dopaminergic regions, compared to MDD, BD and C. | Possible impacts of antipsychotic and antidepressant medications were not quantified. |
| Torrell et al. 2013 (23355257) |
45/15 | SZ: 45 BD: 43 MDD: 47 C: 48 |
SZ: 9/6 BD: 9/6 MDD: 9/6 C: 9/6 |
SZ (15) BD (15) MDD (15) C (15) |
OCtx | qPCR | NR | No differences in mtDNA CN were observed between study groups | NR | MT-ND1 gene expression was increased in BD P vs. C |
| Gu et al. 2013 (24002085) |
14/12 | ASD: 11 C: 11 |
ASD: 11/3 C: 9/3 |
ASD (14) C(12) |
FCtx | RT-PCR | NR | A significant increase of mtDNA CN in ASD subjects compared with C. | MT-ND4 deletion was found in 44% of the ASD group, and 33% of them also had Cyt B deletion. | |
| Tang et al. 2013 (23333625) |
20/25 | ASD: 2–67 C: 2–60 |
ASD: 18/3 C: 22/2 |
ASD (20) C (25) |
TL | MitoChip assay, qPCR | m.7064T>C, Phe387, MT-CO1 | No changes in mtDNA CN (studied in 8 ASD P and 8 C) | No presence of large-scale DELs or duplications. | |
| Sequeira et al. 2012 (22723804) |
3 cohorts Co 1: 4/7 Co 2: 29/6 Co 3: 6/17 |
Co 1: SZ: 53 C: 57 Co 2: SZ: 44 BD: 50 MDD: 51 C: 53 Co 3: SZ: 41 BD: 57 MDD: 41 C: 52 |
Co 1: SZ: 2/3 C: 2/4 Co 2: SZ: 11/3 BD: 9/3 MDD: 11/4 C: 60/16 Co 3: SZ: 2/2 BD: 3/1 MDD: 4/1 C: 16/7 |
Co 1: SZ (5) C (6) Co 2: SZ (14) BD (11) MDD (15) C (76) Co 3: SZ (4) BD (4) MDD (5) C (10) |
Co 1: ACCtx, Amg, Cd, DLPFCtx, Ac, OFCtx, Pu, SN, Th Co 2: DLPFCtx Co 3: DLPFCtx |
NGS, Affymetrix 6.0 SNP chip, qPCR |
149 homoplasmic novel or rare variants: 7 not previously reported (5 synonymous variants, 1 in the D-loop, 1 in a tRNA). 88% transitions and 11% transversions. Higher number of transitions and transversions in MDD vs. C and vs. SZ or BD. The m.195T>C, MT-HV2 and m.16519T>C, D-Loop were underrepresented in pooled SZ and BD vs. C. |
NR | In the DLPFCtx, the common DEL levels were significantly increased in P with BD, marginally increased in P with MDD and not increased in P with SZ vs. C. Higher levels of the common DEL in SN and Cd. The common DEL levels were correlated with age |
Certain brain regions accumulated somatic mutations at higher levels than the blood. |
| Ichikawa et al. 2012 (22030097) |
28 | 63.1 | 20/8 | SZ | FCtx | Sanger sequencing, allele-specific PCR | Homoplasmic substitutions m.8881T>C and m.9699 A>G were detected exclusively in SZ patients. Unregistered m.6617 C>T and m.9500 C>T substitutions with 50% heteroplasmy were found in a brain sample from a single patient. m.9956 A>G was also found as a homoplasmic variant in a brain sample of an SZ patient, while it was heteroplasmic in controls. | NR | NR | m.7196C>A was detected in SZ patients' brain tissue in both a homoplasmic and heteroplasmic state; it was also detected in blood samples of SZ patients and in blood samples of controls as a homoplasmic variant. |
| Rollins et al. 2009 (19290059) |
41/36 | BD: 50 SZ:45 MDD: 51 C: 53 |
SZ: 11/3 BD: 9/3 MDD: 11/4 C: 31/5 |
SZ (14) BD (12) MDD (15) C (36) |
DLPFCtx | Affymetrix mtDNA resequencing array, SNaPshot and allele-specific RT- PCR |
The rate of synonymous base pair substitutions in the coding regions of the mtDNA was 22% higher in P with SZ vs. C. One MDD P carried a homoplasmic mutation in DLPFC at m.10652T>C, Ile61, MT-ND4L, and two P with SZ showed less than 1% heteroplasmy. Low levels of heteroplasmic nonsynonymous mutations were found in the brain. Several mtDNA variants were significantly associated with specific psychiatric disorders: m.114T>C, m.195C>T, m.10652T>C and m.16300G>A with BD; m.750A>G, 1438A>G and 4769A>G with SZ; and 10652C>T, 14668T>C and 15043A>G with MDD. |
NR | NR | Brain pH was significantly associated with super haplogroup U, K and UK |
| Fuke et al. 2008 (18514404) |
99/48 | NA | NA | SZ (50) BD (49) C (48) |
FCtx | RT-qPCR with SYBR Green | NR | NR | Age- and sex-dependent accumulation of the common DEL, independent of the diagnosis. One P with SZ showed high levels of the common DEL |
|
| Sabunciyan et al. 2007 (17195919) |
100/44 | ≤ 68 | NA | SZ (45) BD (40) MDD (15) C (44) |
PFCtx | qPCR, RT-PCR with TagMan and SYBR Green | NR | No significant difference in mtDNA CN level between C and P | No significant difference in the amount of the common DEL between C and P with SZ or BD | Female BD patients had significantly less common DEL (p=0.03) compared with male patients. |
| Vawter et al. 2006 (16636682) |
20/20 | BD: 54 MDD: 51 C: 53 |
P: 14/6 C: 14/6 |
BD (9) MDD (11) C (20) |
ACCtx, DLPFCtx, Cb |
qPCR | NR | NR | NR | mtDNA gene expression increased with agonal duration |
| Munakata et al. 2005 (15737668) |
43/14 | SZ: 44 BD: 42 MDD: 47 C:49 |
SZ: 7/6 BD: 9/6 MDD: 9/6 C: 9/5 |
SZ (13) BD (15) MDD (15) C (14) |
PFCtx | PNA-clamped PCR-RFLP | m.3243A>G, MT-TL1, detected in two BD (mutation load range 0.90–1.00%) and one SZ (0.60%). | NR | NR | LARS2 was upregulated in cybrids carrying the m.3243A>G, MT-TL1 |
| Marchbanks et al. 2003 (14623372) |
15/9 | 70/69 | SZ: 10/5 C: 5/4 |
SZ (15) | NA | PCR-RFLP | m.12027T>C, Ile423Thr, MT-ND4 mutation load of 54% in SZ P vs. 58% in C. | NR | NR | NR |
| Kato et al. 1997 (9359971) |
16/9 | BD: 45 SV: 39 C: 40 |
BD: 3/4 SV: 4/5 C: 4/5 |
BD (7) SV (9) C (9) |
CbCtx | qPCR | NR | NR | The ratio of the common DEL was significantly higher in BD (0.23) compared with that in age-matched C (0.06; p < 0.05). | No significant difference in the common DEL ratio between SVs and controls. Antidepressant was found in the blood of 5 SVs. |
| Cavelier et al. 1995 (8530074) |
13/9 | 80/73 | SZ: 7/6 C: 5/4 |
SZ (13) | FG, Cd | Competitive PCR | NR | NR | No accumulation of the common DEL with age in Cd and a decrease in FG. Lack of age-related accumulation of the DEL. Higher DEL levels in Cd compared to FG. |
No correlation between COX activity and levels of common DEL. |
C: control; Co: cohort; DEL: deletion; F: female; M: male; mtDNA CN: mitochondrial DNA copy number; N: number of subjects; NA: information not available; NR: not reported; P: patient; y: years.
ADO: alcohol/drug abuse/other psychiatric symptoms; ASD: autism spectrum disorder; BD: bipolar disorder; MDD: major depressive disorder; SV: suicide victims; SZ: schizophrenia; KSS: Kerns-Sayre syndrome.
Ac: nucleus accumbens; ACCtx: anterior cingulate cortex; Amg: amigdala; BA24: Brodmann area 24; Cb: cerebellum; CbCtx: cerebellar cortex; Cd: caudate nucleus; DLPFCtx: dorsolateral prefrontal cortex; FCtx: frontal cortex; FG: frontal gyrus; Hi: hippocampus; OCtx: occipital cortex; OFCtx: orbitofrontal cortex; PFCtx: prefrontal cortex; Pu: putamen; SN: substantia nigra; Th: thalamus; TL: temporal lobe.
NGS: next-generation sequencing; PNA: peptide nucleic acid; qPCR: quantitative real-time polymerase chain reaction; RFLP: restriction fragment length polymorphism; RT-qPCR: reverse transcription qPCR.
CO1: cytochrome c oxidase I; COX: cytochrome c oxidase; D-loop: displacement loop; HV2: hypervariable segment 2; LARS2: Leucyl-tRNA synthetase 2; MT-: mitochondrially encoded gene; ND1: NADH-ubiquinone oxidoreductase subunit 1; ND4: NADH-ubiquinone oxidoreductase subunit 4; ND4L: NADH-ubiquinone oxidoreductase subunit 4L; TL1: tRNA-Leu 1.