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Differential susceptibility of retinal neurons to the loss of mitochondrial biogenesis factor Nrf1

ABSTRACT: The retina, the accessible part of the central nervous system, has served as a model system to study the relationship between energy utilization and metabolite supply. When the metabolite supply cannot match the energy demand, retinal neurons are at risk of death. As the powerhouse of eukaryotic cells, mitochondria play a pivotal role in generating ATP, produce precursors for macromolecules, maintain the redox homeostasis, and function as waste management centers for various types of metabolic intermediates. Mitochondrial dysfunction has been implicated in the pathologies of a number of degenerative retinal diseases. It is well known that photoreceptors are particularly vulnerable to mutations affecting mitochondrial function due to their high energy demand and susceptibility to oxidative stress. However, it is unclear how defective mitochondria affect other retinal neurons. Nuclear respiratory factor 1 (Nrf1) is the major transcriptional regulator of mitochondrial biogenesis, and loss of Nrf1 leads to defective mitochondria biogenesis and eventually cell death. Here, we investigated how different retinal neurons respond to the loss of Nrf1. We provide in vivo evidence that the disruption of Nrf1-mediated mitochondrial biogenesis results in a slow, progressive degeneration of all retinal cell types examined, although they present different sensitivity to the deletion of Nrf1, which implicates differential energy demand and utilization, as well as tolerance to mitochondria defects in different neuronal cells. Furthermore, transcriptome analysis on rod-specific Nrf1 deletion uncovered a previously unknown role of Nrf1 in maintaining genome stability.

ORGANISM(S): Mus musculus

PROVIDER: GSE150258 | GEO | 2022/12/17

REPOSITORIES: GEO

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Project description:Mutations in the E3 ubiquitin ligase Parkin cause autosomal recessive Parkinson’s disease. In concert with PINK1, Parkin regulates the clearance of dysfunctional mitochondria via lysosomes. In response, new mitochondria are generated through an interplay of nuclear- and mitochondrial-encoded proteins. Mouse and overexpression models suggests that Parkin also influences these processes, both in the nuclear cascade and at the level of the mitochondrial genome. Additionally, Parkin has been shown to prevent mitochondrial membrane permeation, impeding the escape of mitochondrial DNA (mtDNA). In line with this, serum from Parkin mutation carriers showed higher levels of circulating cell-free mtDNA (ccf-mtDNA) and inflammatory cytokines – a result of the innate immune response - which can be triggered by cytosolic mtDNA. However, Parkin’s relationship with the mitochondrial genome and the mitogenesis pathway has not been explored in patient-derived neurons. To investigate this aspect of Parkin’s cellular function endogenously, we generated induced pluripotent stem cell (iPSC)-derived midbrain neurons from Parkin mutation carriers and healthy controls. In Parkin-deficient cells, several factors in the mitochondrial biogenesis pathway were significantly reduced, resulting in impaired mtDNA homeostasis - a phenomenon that was exacerbated in dopaminergic neurons. Moreover, in response to a lack of freely accessible NAD+, the energy sensor Sirtuin 1, which simultaneously controls mtDNA maintenance processes and mitophagy, was downregulated in Parkin-deficient neurons. However, while impaired lysosomal degradation of mitochondria was only detectable in oxidative conditions, biogenesis defects were already apparent in untreated patient neurons. This may suggest that mitophagy disruption occurs in response to acute stress. By contrast, the biogenesis pathway may be continually impaired in Parkin-associated Parkinson’s disease. Next, using a mutagenic stress model in combination with Parkin knockdown, we detected an increase in ccf-mtDNA and the cytosolic DNA sensor cGAS. To explore if ccf-mtDNA can act as damage-associated molecular pattern in the brain, we used postmortem tissue from a Parkin mutation carrier and performed single-cell RNA sequencing. In the midbrain lacking Parkin, we found a higher percentage of microglia along with an upregulation of proinflammatory cytokines in these cells. Together, our findings suggest a role for Parkin in the control of mitochondrial biogenesis and mtDNA maintenance, which protects midbrain neurons from neuroinflammation-induced degeneration. Future research in iPSC-derived neuron-microglia co-culture systems could aim at developing PD treatment approaches that target the neuronal release or microglial uptake of ccf-mtDNA.

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Differential susceptibility of retinal neurons to the loss of mitochondrial biogenesis factor Nrf1

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