bims-mitdyn 2024-11-24 papers

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

Nat Commun. 2024 Nov 16. 15(1): 9945

NOTCH1 mitochondria localization during heart development promotes mitochondrial metabolism and the endothelial-to-mesenchymal transition in mice.

Jie Wang, Rui Zhao, Sha Xu, Xiang-Yu Zhou, Ke Cai, Yu-Ling Chen, Ze-Yu Zhou, Xin Sun, Yan Shi, Feng Wang, Yong-Hao Gui, Hui Tao, Jian-Yuan Zhao.

Notch signaling activation drives an endothelial-to-mesenchymal transition (EndMT) critical for heart development, although evidence suggests that the reprogramming of endothelial cell metabolism can regulate endothelial function independent of canonical cell signaling. Herein, we investigated the crosstalk between Notch signaling and metabolic reprogramming in the EndMT process. Biochemically, we find that the NOTCH1 intracellular domain (NICD1) localizes to endothelial cell mitochondria, where it interacts with and activates the complex to enhance mitochondrial metabolism. Targeting NICD1 to mitochondria induces more EndMT compared with wild-type NICD1, and small molecule activation of PDH during pregnancy improves the phenotype in a mouse model of congenital heart defect. A NOTCH1 mutation observed in non-syndromic tetralogy of Fallot patients decreases NICD1 mitochondrial localization and subsequent PDH activity in heart tissues. Altogether, our findings demonstrate NICD1 enrichment in mitochondria of the developing mouse heart, which induces EndMT by activating PDH and subsequently improving mitochondrial metabolism.

DOI: https://doi.org/10.1038/s41467-024-54407-7

EMBO Mol Med. 2024 Nov 20.

Pathogenic PDE12 variants impair mitochondrial RNA processing causing neonatal mitochondrial disease.

Pathogenic variants in either the mitochondrial or nuclear genomes are associated with a diverse group of human disorders characterized by impaired mitochondrial function. Within this group, an increasing number of families have been identified, where Mendelian genetic disorders implicate defective mitochondrial RNA biology. The PDE12 gene encodes the poly(A)-specific exoribonuclease, involved in the quality control of mitochondrial non-coding RNAs. Here, we report that disease-causing PDE12 variants in three unrelated families are associated with mitochondrial respiratory chain deficiencies and wide-ranging clinical presentations in utero and within the neonatal period, with muscle and brain involvement leading to marked cytochrome c oxidase (COX) deficiency in muscle and severe lactic acidosis. Whole exome sequencing of affected probands revealed novel, segregating bi-allelic missense PDE12 variants affecting conserved residues. Patient-derived primary fibroblasts demonstrate diminished steady-state levels of PDE12 protein, whilst mitochondrial poly(A)-tail RNA sequencing (MPAT-Seq) revealed an accumulation of spuriously polyadenylated mitochondrial RNA, consistent with perturbed function of PDE12 protein. Our data suggest that PDE12 regulates mitochondrial RNA processing and its loss results in neurological and muscular phenotypes.

Keywords: Exome Sequencing; Lactic Acidosis; Mitochondrial Disease; RNA Processing; tRNA

DOI: https://doi.org/10.1038/s44321-024-00172-5

Mol Cell. 2024 Nov 21. pii: S1097-2765(24)00880-3. [Epub ahead of print]84(22): 4261-4263

AMPK: Balancing mitochondrial quality and quantity through opposite regulation of mitophagy pathways.

Hui Jiang.

In this issue of Molecular Cell, Longo et al.1 reveal that AMPK, a regulatory kinase activated by metabolic stress, inhibits NIX/BNIP3-dependent mitophagy to preserve mitochondrial quantity and activates PINK1/Parkin-dependent mitophagy to ensure mitochondrial quality.

DOI: https://doi.org/10.1016/j.molcel.2024.10.040

Trends Biochem Sci. 2024 Nov 21. pii: S0968-0004(24)00254-8. [Epub ahead of print]

Textbook oxidative phosphorylation needs to be rewritten.

Alicia J Kowaltowski, Fernando Abdulkader.

Oxidative phosphorylation (OxPhos) is the energy-transfer process that generates most of our ATP, fueled by proton and electrical gradients across the inner mitochondrial membrane. A new surprising finding by Hernansanz-Agustín et al. demonstrates that between one-third and half of this gradient is attributable to Na+, transported in exchange for protons within complex I.

Keywords: complex I; ion transport; mitochondria; oxidative phosphorylation; sodium–proton exchange

DOI: https://doi.org/10.1016/j.tibs.2024.11.002

Commun Biol. 2024 Nov 21. 7(1): 1551

Endogenous mitochondrial NAD(P)H fluorescence can predict lifespan.

Christopher S Morrow, Pallas Yao, Carlos A Vergani-Junior, Praju Vikas Anekal, Paula Montero Llopis, Jeffrey W Miller, Bérénice A Benayoun, William B Mair.

Many aging clocks have recently been developed to predict health outcomes and deconvolve heterogeneity in aging. However, existing clocks are limited by technical constraints, such as low spatial resolution, long processing time, sample destruction, and a bias towards specific aging phenotypes. Therefore, here we present a non-destructive, label-free and subcellular resolution approach for quantifying aging through optically resolving age-dependent changes to the biophysical properties of NAD(P)H in mitochondria through fluorescence lifetime imaging (FLIM) of endogenous NAD(P)H fluorescence. We uncover age-dependent changes to mitochondrial NAD(P)H across tissues in C. elegans that are associated with a decline in physiological function and construct non-destructive, label-free and cellular resolution models for prediction of age, which we refer to as "mito-NAD(P)H age clocks." Mito-NAD(P)H age clocks can resolve heterogeneity in the rate of aging across individuals and predict remaining lifespan. Moreover, we spatiotemporally resolve age-dependent changes to mitochondria across and within tissues, revealing multiple modes of asynchrony in aging and show that longevity is associated with a ubiquitous attenuation of these changes. Our data present a high-resolution view of mitochondrial NAD(P)H across aging, providing insights that broaden our understanding of how mitochondria change during aging and approaches which expand the toolkit to quantify aging.

DOI: https://doi.org/10.1038/s42003-024-07243-w

Trends Immunol. 2024 Nov 20. pii: S1471-4906(24)00272-2. [Epub ahead of print]

Nanotube-mediated mitochondrial transfer: power to the T cells!

Cosima T Baldari.

The success of T cell-based immunotherapies is limited by exhaustion, which is associated with mitochondrial dysfunction. Baldwin and colleagues show that bone marrow stromal cells (BMSCs) use nanotubes to transfer mitochondria to T cells, which increases mitochondria mass and fitness and boosts antitumor efficacy. The results pave the way to organelle-based therapies against cancer.

DOI: https://doi.org/10.1016/j.it.2024.11.001