bims-mecosi 2024-11-24 papers

Issue of 2024–11–24
four papers selected by
Verena Kohler, Umeå University

J Cell Biol. 2024 Dec 02. pii: e202407193. [Epub ahead of print]223(12):

PINK1 controls RTN3L-mediated ER autophagy by regulating peripheral tubule junctions.

Ravi Chidambaram, Kamal Kumar, Smriti Parashar, Gowsalya Ramachandran, Shuliang Chen, Susan Ferro-Novick.

Here, we report that the RTN3L-SEC24C endoplasmic reticulum autophagy (ER-phagy) receptor complex, the CUL3KLHL12 E3 ligase that ubiquitinates RTN3L, and the FIP200 autophagy initiating protein, target mutant proinsulin (Akita) condensates for lysosomal delivery at ER tubule junctions. When delivery was blocked, Akita condensates accumulated in the ER. In exploring the role of tubulation in these events, we unexpectedly found that loss of the Parkinson's disease protein, PINK1, reduced peripheral tubule junctions and blocked ER-phagy. Overexpression of the PINK1 kinase substrate, DRP1, increased junctions, reduced Akita condensate accumulation, and restored lysosomal delivery in PINK1-depleted cells. DRP1 is a dual-functioning protein that promotes ER tubulation and severs mitochondria at ER-mitochondria contact sites. DRP1-dependent ER tubulating activity was sufficient for suppression. Supporting these findings, we observed PINK1 associating with ER tubules. Our findings show that PINK1 shapes the ER to target misfolded proinsulin for RTN3L-SEC24C-mediated macro-ER-phagy at defined ER sites called peripheral junctions. These observations may have important implications for understanding Parkinson's disease.

DOI: https://doi.org/10.1083/jcb.202407193

Biochem Biophys Res Commun. 2024 Nov 12. pii: S0006-291X(24)01526-2. [Epub ahead of print]739 150990

Promyelocytic leukemia protein (PML) knockout increases mitochondrial Ca2+ uptake in HeLa cells.

R R Sharipov, A M Surin, S A Silonov, E Y Smirnov, M V Neklesova, I E Vishnyakov, A A Gavrilova, A A Mikryukova, A A Moskovtsev, Z V Bakaeva, S S Kolesnikov, I M Kuznetsova, K K Turoverov, A V Fonin.

The multifunctional promyelocytic leukemia protein (PML) is involved in the regulation of various cellular processes in both physiological and pathological conditions. Specifically, PML is one of the inositol-1,4,5-trisphosphate receptors (IP3Rs) activity regulators and can influence Ca2+ transport from the endoplasmic reticulum (ER) to mitochondria. In this work, the effects of PML knockout on calcium homeostasis in the cytosol, ER, and mitochondria of HeLa cells were studied upon stimulation with histamine, which induces Ca2+ mobilization from the ER via IP3Rs. We utilized calcium indicators with different subcellular localizations, including synthetic dyes Fura-2 (cytosolic), Xrhod-5F (mitochondrial), and protein sensor R-CEPIAer (ER), as well as mitochondrial potential-sensitive probes Rh123 and TMRM. Our results show that PML knockout induced changes in HeLa cell and mitochondrial morphology, slightly decreased basal and integral Ca2+ levels, enhanced mitochondrial Ca2+ uptake from the cytoplasm, and maintained residual mitochondrial potential after depolarization. Additionally, it reduced the Ca2+ pool in ER membranes not associated with histamine receptor activation and, consequently, IP3Rs. These findings suggest that changes in calcium ion transport due to PML knockout in HeLa cells affect mitochondrial activity.

Keywords: Endoplasmic reticulum; Fluorescence microscopy; Intracellular calcium; Mitochondria; Mitochondria-associated membranes (MAMs)

DOI: https://doi.org/10.1016/j.bbrc.2024.150990

Mol Neurobiol. 2024 Nov 19.

The Role of Cardiolipin in Brain Bioenergetics, Neuroinflammation, and Neurodegeneration.

Patrick C Bradshaw, Jessa L Aldridge, Leah E Jamerson, Canah McNeal, A Catherine Pearson, Chad R Frasier.

Cardiolipin (CL) is an essential phospholipid that supports the functions of mitochondrial membrane transporters and oxidative phosphorylation complexes. Due to the high level of fatty acyl chain unsaturation, CL is prone to peroxidation during aging, neurodegenerative disease, stroke, and traumatic brain or spinal cord injury. Therefore, effective therapies that stabilize and preserve CL levels or enhance healthy CL fatty acyl chain remodeling are needed. In the last few years, great strides have been made in determining the mechanisms through which precursors for CL biosynthesis, such as phosphatidic acid (PA), are transferred from the ER to the outer mitochondrial membrane (OMM) and then to the inner mitochondrial membrane (IMM) where CL biosynthesis takes place. Many neurodegenerative disorders show dysfunctional mitochondrial ER contact sites that may perturb PA transport and CL biosynthesis. However, little is currently known on how neuronal mitochondria regulate the synthesis, remodeling, and degradation of CL. This review will focus on recent developments on the role of CL in neurological disorders. Importantly, due to CL species in the brain being more unsaturated and diverse than in other tissues, this review will also identify areas where more research is needed to determine a complete picture of brain and spinal cord CL function so that effective therapeutics can be developed to restore the rates of CL synthesis and remodeling in neurological disorders.

Keywords: Alzheimer’s; Cardiolipin; Cell death; Inflammation; Mitochondria; Parkinson’s

DOI: https://doi.org/10.1007/s12035-024-04630-6

J Agric Food Chem. 2024 Nov 21.

β-Carotene Ameliorates LPS-Induced Endoplasmic Reticulum Stress and Mitochondrial Disorder by Targeting ORAI1 in Bovine Mammary Epithelial Cells.

Meijuan Meng, Xuerui Li, Shendong Zhou, Xiaoli Shi, Xiangzhen Shen, Guangjun Chang.

Ca2+ is an important regulator of endoplasmic reticulum (ER) and mitochondrial function. Store-operated calcium entry (SOCE) serves as the predominant pathway for the influx of extracellular Ca2+ into the cell. ORAI1, ORAI2, and ORAI3 are the main proteins of SOCE. Ca2+ disturbance leads to ER stress and mitochondrial damage. β-Carotene (β-C) is a precursor of vitamin A and has anti-inflammatory and antioxidant effects. However, it remains unclear if β-C mitigates ER stress and mitochondrial dysfunction triggered by LPS and its underlying molecular mechanisms have not been fully elucidated in bovine mammary epithelial cells (BMECs). Therefore, the experiment aimed to explore the protective mechanism of β-C. Results showed that LPS increased the ORAI1 expression, and caused ER stress by upregulating the expression of ER stress-related genes and proteins in BMECs. LPS also caused mitochondrial dysfunction by decreasing mitochondrial fusion proteins and increasing mitochondrial division and apoptosis proteins. Silencing ORAI1 mitigated ER stress and mitochondrial impairment caused by LPS. Conversely, elevated ORAI1 levels induced similar stress and damage in BMECs. β-C pretreatment resulted in diminished ORAI1 expression and a reduction in ER stress and mitochondrial dysfunction triggered by LPS. However, ORAI1 overexpression blocked the protective effects of β-C. In conclusion, β-C alleviated the LPS-induced ER stress and mitochondria dysfunction in an ORAI1-dependent manner. Our findings provide a mechanistic basis for further exploration of the regulatory effects of β-C on mammary injuries.

Keywords: LPS; ORAI1; bovine mammary epithelial cells; endoplasmic reticulum stress; mitochondrial dysfunction; β-carotene

DOI: https://doi.org/10.1021/acs.jafc.4c06875