Loss of mtDNA activates astrocytes and leads to spongiotic encephalopathy

Abstract

Mitochondrial dysfunction manifests as different neurological diseases, but the mechanisms underlying the clinical variability remain poorly understood. To clarify whether different brain cells have differential sensitivity to mitochondrial dysfunction, we induced mitochondrial DNA (mtDNA) depletion in either neurons or astrocytes of mice, by inactivating Twinkle (TwKO), the replicative mtDNA helicase. Here we show that astrocytes, the most abundant cerebral cell type, are chronically activated upon mtDNA loss, leading to early-onset spongiotic degeneration of brain parenchyma, microgliosis and secondary neurodegeneration. Neuronal mtDNA loss does not, however, cause symptoms until 8 months of age. Findings in astrocyte-TwKO mimic neuropathology of Alpers syndrome, infantile-onset mitochondrial spongiotic encephalopathy caused by mtDNA maintenance defects. Our evidence indicates that (1) astrocytes are dependent on mtDNA integrity; (2) mitochondrial metabolism contributes to their activation; (3) chronic astrocyte activation has devastating consequences, underlying spongiotic encephalopathy; and that (4) astrocytes are a potential target for interventions.

Astrocyte‐specific deletion of the mitochondrial m‐AAA protease reveals glial contribution to neurodegeneration

“…Both this study and the work of Ignatenko et al (2018) highlight how mitochondrial dysfunction in astrocytes can have downstream effects on neuronal function and survival. We show here that decreasing the levels of the m-AAA protease in BG is sufficient to cause noncell-autonomous morphological degeneration and to change the electrophysiological properties of PCs.…”

“…Astrocyte‐specific deletion of Cox10 , a complex IV assembly factor, despite leading to complex IV deficiency and a respiratory deficit, caused neither cell death nor secondary neuronal degeneration, but rather increased the glycolytic metabolism of the cells (Supplie et al, ). In contrast, inactivation of the helicase Twinkle specifically in astrocytes, leading to OXPHOS deficiency and loss of mtDNA, induced a chronic activation of astrocytes, causing spongiosis, loss of neurons, and inflammation (Ignatenko et al, ). In this study, we did not find evidence of respiratory deficiency, but also observed cell‐autonomous activation of targeted astrocytes and infiltration of microglia.…”

Loss of the mitochondrial i ‐ AAA protease YME 1L leads to ocular dysfunction and spinal axonopathy

“…Locomotor control depends on the integration of neurons in the brain. An impaired locomotor activity correlates with brain atrophy and inflammation in many mitochondrial diseases (Maltecca et al, 2009;Almajan et al, 2012;Johnson et al, 2013;Ignatenko et al, 2018). We therefore analyzed brain morphology and brain weight in NYKO mice.…”

β‐ RA reduces DMQ /CoQ ratio and rescues the encephalopathic phenotype in Coq9 R239X mice

“…This strategy was partially successful in vitro in COQ7 null yeasts, as well as in mouse and human fibroblasts with mutations in COQ7 or COQ9 (Xie et al , ; Freyer et al , ; Luna‐Sanchez et al , ). Additionally, β‐RA is a structural analogue of salicylic acid (2‐hydroxybenzoic acid), an anti‐inflammatory molecule that may be potentially valuable to reduce the neuroinflammation (Lan et al , ; Gomez‐Guzman et al , ), a factor that has been recently postulated as an essential pathomechanism and a therapeutic target in mitochondrial encephalopathies (Ignatenko et al , ), leukoencephalopathy, and neurodegenerative diseases (Eto et al , ; Liddelow & Barres, , ). Also salicylic derivate, known as salicylates, may act as mTOR inhibitors (Cameron et al , ), and this action may be therapeutic in mitochondrial diseases (Johnson et al , ).…”