bims-midbra 2022-02-13 papers

Issue of 2022‒02‒13
four papers selected by
Ana Paula Mendonça
University of Padova

J Cell Sci. 2022 Feb 01. pii: jcs248534. [Epub ahead of print]135(3):

Endoplasmic reticulum-mitochondria signaling in neurons and neurodegenerative diseases.

Andrea Markovinovic, Jenny Greig, Sandra María Martín-Guerrero, Shaakir Salam, Sebastien Paillusson.

Recent advances have revealed common pathological changes in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis with related frontotemporal dementia (ALS/FTD). Many of these changes can be linked to alterations in endoplasmic reticulum (ER)-mitochondria signaling, including dysregulation of Ca2+ signaling, autophagy, lipid metabolism, ATP production, axonal transport, ER stress responses and synaptic dysfunction. ER-mitochondria signaling involves specialized regions of ER, called mitochondria-associated membranes (MAMs). Owing to their role in neurodegenerative processes, MAMs have gained attention as they appear to be associated with all the major neurodegenerative diseases. Furthermore, their specific role within neuronal maintenance is being revealed as mutant genes linked to major neurodegenerative diseases have been associated with damage to these specialized contacts. Several studies have now demonstrated that these specialized contacts regulate neuronal health and synaptic transmission, and that MAMs are damaged in patients with neurodegenerative diseases. This Review will focus on the role of MAMs and ER-mitochondria signaling within neurons and how damage of the ER-mitochondria axis leads to a disruption of vital processes causing eventual neurodegeneration.

Keywords: Endoplasmic reticulum; MAMs; Mitochondria; Neurodegenerative diseases; Neurons; Tethers

DOI: https://doi.org/10.1242/jcs.248534

Neurochem Int. 2022 Feb 05. pii: S0197-0186(22)00023-7. [Epub ahead of print]154 105298

PINK1 regulates mitochondrial fission/fusion and neuroinflammation in β-amyloid-induced Alzheimer's disease models.

Xiaojuan Wang, Yongqiang Xue, Yang Yao, Yang Li, Xuefei Ji, Tianyan Chi, Peng Liu, Libo Zou.

Disrupted mitochondrial fission/fusion balance is consistently involved in neurodegenerative diseases, including Alzheimer's disease. PTEN-induced putative kinase 1 (PINK1), a mitochondrial kinase, has been reported to prevent mitochondrial injury, oxidative stress, apoptosis, and inflammation. However, to the best of our knowledge, the contribution of PINK1 to Aβ-induced mitochondrial fission/fusion has not been reported. In the present study, we showed that PINK1 deficiency promoted mitochondrial fission and fusion, aggravated mitochondrial dysfunction, and promoted neuroinflammatory cytokine factor production induced by intracerebroventricular (ICV) injection of Aβ25-35 in rats. In vitro experiments have also showed that Aβ25-35 caused more severe cell injury in PINK1-knockdown PC12 cells. These cells suffered more extensive death when exposed to proinflammatory cytokines. Lastly, we found that PINK1 overexpression significantly inhibited mitochondrial fusion, improved mitochondrial dysfunction, and reduced neuroinflammatory cytokine production induced by Aβ25-35. The current study suggests the involvement of PINK1 in Aβ25-35-mediated mitochondrial dynamics and that PINK1 may be a potential target for therapies aimed at enhancing neuroprotection to ameliorate Aβ25-35-induced insults.

Keywords: Alzheimer's disease; Mitochondrial fission and fusion; Neuroinflammation; PINK1; β-Amyloid

DOI: https://doi.org/10.1016/j.neuint.2022.105298

Mol Cell Neurosci. 2022 Feb 04. pii: S1044-7431(22)00010-0. [Epub ahead of print] 103704

Intermitochondrial signaling regulates the uniform distribution of stationary mitochondria in axons.

Nozomu Matsumoto, Ikuma Hori, Masashi K Kajita, Tomoya Murase, Wataru Nakamura, Takahiro Tsuji, Seiji Miyake, Masaru Inatani, Yoshiyuki Konishi.

In the central nervous system (CNS), many neurons develop axonal arbors that are crucial for information processing. Previous studies have demonstrated that premature axons contain motile and stationary mitochondria, and their balance is important for axonal arborization. However, the mechanisms by which neurons determine the positions of stationary mitochondria as well as their turnover remain to be elucidated. We observed that the distribution of stationary mitochondrial spots along the unmyelinated and nonsynaptic axons is not random but rather relatively uniform both in primary cultured neurons and in tissues. Intriguingly, whereas the positions of each mitochondrial spot changed over time, the overall distribution remained uniform. In addition, local inactivation of mitochondria by KillerRed mediated chromophore-assisted light inactivation (CALI) inhibited the translocation of mitochondrial spots in adjacent axonal regions, suggesting that functional mitochondria enhance the motility of other mitochondria in the vicinity. Signals of ATP:ADP sensor, PercevalHR indicated that the ATP:ADP ratio was relatively high around mitochondria, and treating axons with phosphocreatine (PCr), which supplies ATP, reduced the immobile mitochondria induced by the local mitochondrial inactivation. In a mathematical model, we found that the ATP gradient generated by mitochondria, and ATP dependent regulation of mitochondrial motility could establish uniform mitochondrial distribution. These observations suggest that axons in the CNS possess the system that distributes mitochondria uniformly, and intermitochondrial signaling contribute to the regulation. In addition, our results suggest the possibility that ATP might be one of the molecules mediating the signaling.

Keywords: ATP; Axonal transport; Cerebellar granule neurons; Mitochondrial distribution; Retinal ganglion cells; Stationary mitochondria

DOI: https://doi.org/10.1016/j.mcn.2022.103704

Diabetes. 2022 Feb 08. pii: db210983. [Epub ahead of print]

PACS-2 Ameliorates Tubular Injury by Facilitating Endoplasmic Reticulum-Mitochondria Contact and Mitophagy in Diabetic Nephropathy.

Mitochondria-associated endoplasmic reticulum membrane (MAM) is emerging as a novel insight into tubular injury in diabetic nephropathy (DN), but the precise mechanism remains unclear. Here, we demonstrate that the expression of phosphofurin acidic cluster sorting protein 2 (PACS-2), a critical regulator of MAM formation, is significantly decreased in renal tubules of patients with DN, which is positively correlated with renal function and negatively correlated with degrees of tubulointerstitial lesions. Conditional deletion of Pacs-2 in proximal tubules (PT) aggravates albuminuria and tubular injury in streptozotocin (STZ)-induced diabetic mice. Mitochondrial fragmentation, MAM disruption and defective mitophagy accompanied by altered expression of mitochondrial dynamics and mitophagic protein including DRP1 and BECN1 are observed in tubules from diabetic mice, while these changes are more pronounced in PT-specific Pacs-2 knockout mice. In vitro, overexpression of PACS-2 in HK-2 cells alleviates excessive mitochondrial fission induced by high glucose through blocking mitochondrial recruitment of DRP1, and subsequently restores MAM integrity and enhances mitophagy. Mechanistically, PACS-2 binds to BECN1 and mediates the relocalization of BECN1 to MAM where it promotes the formation of mitophagosome. Together, these data highlight an important but previously unrecognized role of PACS-2 in ameliorating tubular injury in DN by facilitating MAM formation and mitophagy.

DOI: https://doi.org/10.2337/db21-0983