Abstract
sMutations in pitrilysin metallopeptidase 1 (PITRM1), a mitochondrial protease involved in mitochondrial precursor processing and degradation, result in a slow-progressing syndrome characterized by cerebellar ataxia, psychotic episodes, and obsessive behavior, as well as cognitive decline. To investigate the pathogenetic mechanisms of mitochondrial presequence processing, we employed cortical neurons and cerebral organoids generated from PITRM1-knockout human induced pluripotent stem cells (iPSCs). PITRM1 deficiency strongly induced mitochondrial unfolded protein response (UPRmt) and enhanced mitochondrial clearance in iPSC-derived neurons. Furthermore, we observed increased levels of amyloid precursor protein and amyloid β in PITRM1-knockout neurons. However, neither cell death nor protein aggregates were observed in 2D iPSC-derived cortical neuronal cultures. On the other hand, over time, cerebral organoids generated from PITRM1-knockout iPSCs spontaneously developed pathological features of Alzheimer’s disease (AD), including the accumulation of protein aggregates, tau pathology, and neuronal cell death. Single-cell RNA sequencing revealed a perturbation of mitochondrial function in all cell types in PITRM1-knockout cerebral organoids, whereas immune transcriptional signatures were substantially dysregulated in astrocytes. Importantly, we provide evidence of a protective role of UPRmt and mitochondrial clearance against impaired mitochondrial presequence processing and proteotoxic stress. Here, we propose a novel concept of PITRM1-linked neurological syndrome whereby defects of mitochondrial presequence processing induce an early activation of UPRmt that, in turn, modulates cytosolic quality control pathways. Thus, our work supports a mechanistic link between mitochondrial function and common neurodegenerative proteinopathies.
Highlights
These authors contributed : María José Pérez, Dina Ivanyuk
To address the impact of pitrilysin metallopeptidase 1 (PITRM1) on the function of human neurons, we differentiated PITRM1+/+ and PITRM1−/− induced pluripotent stem cells (iPSCs) into neuronal cultures that were enriched for cortical neurons; we assessed the neuronal cultures at 35 and 65 days in vitro (DIV)
A decreased ratio of processed, mature to immature frataxin was detected in PITRM1−/− iPSC-derived neural progenitor cells (NPCs) and neurons (Supplementary Fig. 1i, j), indicating the impaired function of matrix presequence peptidase (MPP) and defects of mitochondrial presequence processing
Summary
Patients suffer from progressive cerebellar dysfunction leading to cerebellar atrophy, with psychiatric manifestations including obsessive behavior, anger attacks, and psychosis [2, 3] Some of these patients showed a deterioration of their cognitive functions with a slow progression until their late sixties [2, 3]. PITRM1-deficient mice exhibit an age-dependent accumulation of amyloid precursor protein (APP) and Aβ deposits within the brain [2], suggesting a link between defects of mitochondrial proteostasis and adult-onset neurodegenerative dementia. Identifying the mechanisms that lead to neurodegeneration in primary mitochondrial diseases characterized by defects of mitochondrial proteostasis, such as PITRM1-linked neurological syndrome, may help clarify the long-debated but still unresolved involvement of altered mitochondrial function in neurodegenerative dementia. To examine PITRM1-related pathogenetic mechanisms, we generated PITRM1-knockout human induced pluripotent stem cells (iPSCs) and examined the role of mitochondrial function and proteostasis using 2D neuronal and 3D brain-organoid model systems
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