Table 1.

The mitochondrial epigenome and noncoding genome in aging and brain diseases

Condition	Regulatory layer	Model	Main findings	Ref.
Aging	mtDNA methylation	Human postmortem brain	mtDNA CpG and non-CpG methylation increases with age	[37,38]
		C. elegans	mtDNA 6mA dysregulation alters mtDNA copy number and transcript levels	[39]
	Noncoding RNAs	Human peripheral mononuclear blood cells	Altered mecciRNA profiles including reduced circMT-RNR2	[42]
		Human fibroblasts	CircMT-RNR2 promotes mitochondrial function and suppresses senescence	[42]
	Cytosolic mtDNA / mt-dsRNA	Aged mouse brain/primary microglia	Cytosolic mtDNA activates microglial cGAS–STING signaling	[13]
		Aged mouse brain	Cytosolic mt-dsRNA activates RIG-I/MDA5 signaling	[12]
		Aged mouse brain/primary neurons	SEC61A1 promotes neuronal mt-dsRNA release and cognitive decline	[9]
AD	mtDNA methylation	Human AD peripheral blood/plasma cell-free DNA	Circulating mtDNA D-loop cytosine methylation profiles are associated with mild cognitive decline and AD progression	[50–53]
	Noncoding RNAs	Human postmortem AD brain; AD mouse model and primary neurons	lncMtloop levels are reduced in AD, lncMtloop restoration improves mitochondrial function and AD-related pathology	[10]
	Cytosolic mtDNA / mt-dsRNA	Microglia and endothelial cells in AD mouse models	Cytosolic mtDNA activates cGAS–STING signaling and inflammation	[45–47]
		AD patient and human postmortem AD brains	Cytosolic mt-dsRNA is increased and correlated with worsened neuropathology and cognitive outcomes	[43]
		Human postmortem AD brain/serum; AD mouse model brain	Increased cytosolic double-stranded RNA and SEC61A1 are increased in AD and associated with immune signaling	[9]
PD	mtDNA methylation	Human postmortem PD brain	No association between prefrontal cortex mtDNA cytosine methylation and PD	[63]
		Human PD peripheral blood	D-loop cytosine methylation is increased in PD peripheral blood	[64]
		Human PD peripheral blood/serum	No differential mtDNA cytosine methylation in PD peripheral blood/serum	[65,66]
	Cytosolic mtDNA / mt-dsRNA	Human PD postmortem brain/cell line; PD mouse models	mtDNA damage/release activates STING and inflammasome-associated signaling	[57–60]
		Human PD postmortem brain/ neuronal cell line; PD mouse model; PD zebrafish model	PINK1-related mitophagy defects promote cytosolic mtDNA accumulation	[11,61]
		Human PD postmortem brain	Cytosolic mitochondrial dsDNA is detected and associated with α-synuclein-associated pathology	[11]
HD	Cytosolic mtDNA / mt-dsRNA	Human HD postmortem brain; HD mouse model brain/microglia	Cytosolic mtDNA release is associated with neuroinflammation in HD	[69]
		Human postmortem brain / HD mouse model	Mutant huntingtin promotes neuronal mitochondrial RNA cytoplasmic release and innate immune activation	[71]
Stroke	mtDNA methylation	Human peripheral blood	Higher mtDNA methylation is associated with increased stroke risk	[83]
	NoncodingRNAs	Human plasma	Elevated circulating LIPCAR is associated with neurological impairment and adverse stroke outcomes	[86]
	Cytosolic mtDNA / mt-dsRNA	Rat stroke model; Mouse neuronal cell line	Oxidized mtDNA activates cGAS–STING signaling in the brain and neurons after ischemia-reperfusion	[81]
TBI	mtDNA methylation	Rat TBI model	Increased 5mC disrupts TFAM expression and DNA binding in the brain	[83]
	Cytosolic mtDNA / mt-dsRNA	Mouse TBI model	Neuron-derived mtDNA activates microglia through ZBP1 signaling	[82]