Learning from massive testing of mitochondrial disorders: UPD explaining unorthodox transmission

Tolomeo, Deborah; Rubegni, Anna; Nesti, Claudia; Barghigiani, Melissa; Battini, Roberta; D'Amore, Francesca; Doccini, Stefano; Galatolo, Daniele; Giglio, Sabrina; Guarducci, Silvia; Pantaleo, Marilena; Pasquariello, Rosa; Procopio, Elena; Pochiero, Francesca; Tessa, Alessandra; Santorelli, Filippo M.

doi:10.1136/jmedgenet-2020-107644

Cited by 5 publications

(6 citation statements)

References 11 publications

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“…It was shown that this involves feedback inhibition of MPP 16,26 . Clinically, PITRM1 defects cause progressive forms of neurodegeneration [27][28][29] . Notably, PITRM1 can also degrade other short peptides, including Aβ species which accumulate in the brains of Alzheimer's disease patients 15 and its activity was found to counteract Alzheimer's pathology in a mouse model 30 .…”

Section: Resultsmentioning

confidence: 99%

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DELE1 tracks perturbed protein import and processing in human mitochondria

2022

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Protein homeostatic control of mitochondria is key to age-related diseases and organismal decline. However, it is unknown how the diverse types of stress experienced by mitochondria can be integrated and appropriately responded to in human cells. Here we identify perturbations in the ancient conserved processes of mitochondrial protein import and processing as sources of DELE1 activation: DELE1 is continuously sorted across both mitochondrial membranes into the matrix and detects different types of perturbations along the way. DELE1 molecules in transit can become licensed for mitochondrial release and stress signaling through proteolytic removal of N-terminal sorting signals. Import defects that occur at the mitochondrial surface allow DELE1 precursors to bind and activate downstream factor HRI without the need for cleavage. Genome-wide genetics reveal that DELE1 additionally responds to compromised presequence processing by the matrix proteases PITRM1 and MPP, which are mutated in neurodegenerative diseases. These mechanisms rationalize DELE1-dependent mitochondrial stress integration in the human system and may inform future therapies of neuropathies.

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Section: Resultsmentioning

confidence: 99%

“…1f). Deleterious mutations in PITRM1 have been identified in multiple families suffering from a progressive neurodegenerative phenotype with neurological manifestations [27][28][29] . It has been proposed that loss of PITRM1 installs a cytoprotective response 69 but whether this involves signaling through DELE1 remains unexplored.…”

Section: Resultsmentioning

confidence: 99%

DELE1 tracks perturbed protein import and processing in human mitochondria

2022

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“…The patient's fibroblasts had severely reduced PITRM1 transcript and protein expression, and the measurement of oxygen consumption rates denoted impaired mitochondrial ATP metabolism due to defective OXPHOS [70].…”

Section: Biallelic Mutations In Pitrm1 Are Associated With Complex Phenotypes and Amyloidotic Neurodegenerationmentioning

confidence: 99%

Role of PITRM1 in Mitochondrial Dysfunction and Neurodegeneration

et al. 2021

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Mounting evidence shows a link between mitochondrial dysfunction and neurodegenerative disorders, including Alzheimer Disease. Increased oxidative stress, defective mitodynamics, and impaired oxidative phosphorylation leading to decreased ATP production, can determine synaptic dysfunction, apoptosis, and neurodegeneration. Furthermore, mitochondrial proteostasis and the protease-mediated quality control system, carrying out degradation of potentially toxic peptides and misfolded or damaged proteins inside mitochondria, are emerging as potential pathogenetic mechanisms. The enzyme pitrilysin metallopeptidase 1 (PITRM1) is a key player in these processes; it is responsible for degrading mitochondrial targeting sequences that are cleaved off from the imported precursor proteins and for digesting a mitochondrial fraction of amyloid beta (Aβ). In this review, we present current evidence obtained from patients with PITRM1 mutations, as well as the different cellular and animal models of PITRM1 deficiency, which points toward PITRM1 as a possible driving factor of several neurodegenerative conditions. Finally, we point out the prospect of new diagnostic and therapeutic approaches.

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“…However, while the genetic link between mitochondria, inherited neuropathies and metabolic disorders is well-described and widely observed in clinical practice and experimental biology [ 38 – 42 ], a conclusive causal connection between mitochondria and AD is less well defined, especially if compared to other neurodegenerative diseases, such as Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) [ 43 – 47 ]. Recent clinical findings have reported that missense mutations in the gene encoding pitrilysin metallopeptidase 1 (PITRM1, also known as presequence protease) may cause the accumulation of Aβ-positive deposits [ 48 – 50 ]. A study of a single Norwegian family revealed that patients carrying pathogenic PITRM1 mutations develop progressive spinocerebellar ataxia and functional changes of mitochondrial bioenergetics in muscle biopsy.…”

Section: Introductionmentioning

confidence: 99%

Decoding metabolic signatures in Alzheimer’s disease: a mitochondrial perspective

Bano,

Ehninger,

Bagetta

2023

Cell Death Discov.

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Alzheimer’s disease (AD) is one of the most prevalent age-related neurodegenerative diseases and accounts for the majority of dementia cases worldwide. Tremendous ongoing efforts of basic and clinical research have expanded our knowledge on AD and its complex multifactorial pathogenesis. For sporadic AD, it is widely assumed that silent and early symptomatic stages initiate decades before the irreversible decline in cognitive abilities that ultimately lead to debilitating conditions. In addition to amyloid plaques and tau-containing neurofibrillary tangles as the most prominent hallmarks of AD lesions within the affected brain areas, we now possess a broader collection of pathological signatures that are associated with AD development and progression. In this regard, there is a substantial body of evidence suggesting that hypometabolism occurs in the brains of individuals at the prodromal stage before dementia is diagnosed, which may reflect an early role of metabolic dysfunction in AD. This perspective surveys the vast literature and critically assesses the current evidence demonstrating a mitochondrial contribution to AD. Additionally, we discuss our interpretations of the reported mitochondrial signatures and consider how altered mitochondrial bioenergetics may be an additional risk factor for AD pathogenesis.

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Learning from massive testing of mitochondrial disorders: UPD explaining unorthodox transmission

Cited by 5 publications

References 11 publications

DELE1 tracks perturbed protein import and processing in human mitochondria

DELE1 tracks perturbed protein import and processing in human mitochondria

Role of PITRM1 in Mitochondrial Dysfunction and Neurodegeneration

Decoding metabolic signatures in Alzheimer’s disease: a mitochondrial perspective

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