Table 1.

A summary of studies measuring ccf-mtDNA or mtDNA copy number in neurological disorders.

Disease	Species	Sample	Finding	Ref.
Neurodegenerative diseases
MS	H. sapiens	CSF samples of MS patients	Association between lower ccf-mtDNA and MS and neurodegeneration	[57]
MS	H. sapiens	MS patients’ blood plasma samples	Increased ccf-mtDNA in MS patients compared to healthy patients	[58,59]
MS	H. sapiens	MS patients’ CSF samples	Increased ccf-mtDNA in CSF of MS patients compared to cognitively healthy patients	[60]
MS	H. sapiens	Relapsing-remitting MS patients’ peripheral blood samples	Decreased ccf-mtDNA levels in MS patients’ when compared to healthy patients	[61]
PD	H. sapiens	CSF samples from PD patients	Reduced ccf-mtDNA in CSF from PD patients compared to healthy subjects	[62]
PD	H. sapiens	CSF samples from PD patients	Significant reduction in ccf-mtDNA in PD patients Reduction in ccf-mtDNA associated with type and duration of treatment	[63]
AD	H. sapiens	CSF samples from preclinical AD patients	Lower ccf-mtDNA levels in CSF of preclinical AD patients (several studies failed to replicate results)	[64]
ALS	M. musculus	In vivo study of aberrant TDP-43 transgenic mice	TDP-43 Caused mtDNA release to the cytoplasm via the mPTP	[29]
ALS	H. Sapiens	ALS spinal cord neuron cell line	ALS spinal cord neurons showed significant reductions in mtDNA-cn and mitochondrial gene deletions	[65]
Neuropsychiatric diseases
Addiction	H. sapiens	Methamphetamine-addiction model in human dopaminergic neuroblastoma SH-SY5Y cell line	Decrease in mtDNA-cn Apoptosis after 48 h of treatment	[66]
Addiction	M. musculus	Peripheral blood from murine model of morphine addiction Peripheral blood from heroin addiction patients	Decrease in mtDNA-cn in hippocampi; Melatonin-dosage restored mtDNA-cn	[67]
Anxiety	H. sapiens	Serum samples from a middle-aged cohort	Increased ccf-mtDNA levels with introduction of negative mood stimulus	[68]
MDD	H. sapiens	Plasma samples from suicide attempters	Increased levels of ccf-mtDNA	[69]
MDD	H. sapiens	Plasma samples from unmedicated MDD patients	Elevated ccf-mtDNA levels compared to healthy subjects; No significant difference in peripheral blood mononuclear cells’ mtDNA-cn	[70]
SZ	H. sapiens	Patient blood plasma samples	Increase in ccf-mtDNA in SZ patients; mtDNA release because of exacerbated apoptosis	[71]
SZ BD	H. sapiens	Whole-blood samples of screened patients	Increasing age and psychosis severity correlated with decreasing ccf-mtDNA levels; Risperidone treatments found to have a reducing effect on ccf-mtDNA at concentrations simulating clinical target level in plasma, but not at concentrations simulating CSF or brain interstitial target level	[72]
BD type I (BD-I)	H. sapiens	BD-I patients’ leukocyte samples	Negative association between number of manic-episode relapses and mtDNA-cn	[73]
BD	H. sapiens	Serum samples from an adolescent cohort	No significant difference in ccf-mtDNA levels between groups; Increase in serum lactate levels for adolescents diagnosed with BD	[74]
BD	H. sapiens	Plasma samples from MDD patients	MDD patients showed lower plasma mtDNA levels than healthy patients	[75]
BD	H. sapiens	Serum samples from BD patients	Higher levels of ccf-mtDNA in BD patients	[76]

Table Abbreviations: major depressive disorder (MDD); bipolar disorder (BD); schizophrenia (SZ); multiple sclerosis (MS), Parkinson’s disease (PD), Alzheimer’s disease (AD); cerebrospinal fluid (CSF); mitochondrial DNA copy number (mtDNA-cn); circulating cell free mitochondrial DNA (ccf-mtDNA).