bims-midtic 2024-01-14 papers

bims-midtic

Biomed News

on Mitochondrial dynamics and trafficking in cells

Issue of 2024–01–14
ten papers selected by
Omkar Joshi, Turku Bioscience

Cristae shaping and dynamics in mitochondrial function.
Developmental changes of the mitochondria in the murine anteroventral cochlear nucleus.
Exogenous mitochondrial transfer increases energy expenditure and attenuates adiposity gains in mice with diet-induced obesity.
Arrestin-3 binds parkin and enhances parkin-dependent mitophagy.
Mitochondrial phospholipid transport: Role of contact sites and lipid transport proteins.
Ratiometric fluorescent biosensor for detection and real-time imaging of nitric oxide in mitochondria of living cells.
Emerging roles of mitochondrial functions and epigenetic changes in the modulation of stem cell fate.
A mitochondria-targeting dihydroartemisinin derivative as a reactive oxygen species -based immunogenic cell death inducer.
Paracrine signalling by pancreatic δ cells determines the glycaemic set point in mice.
Local and dynamic regulation of neuronal glycolysis in vivo.

J Cell Sci. 2024 Jan 01. pii: jcs260986. [Epub ahead of print]137(1):

Cristae shaping and dynamics in mitochondrial function.

Claire Caron, Giulia Bertolin.

  Mitochondria are multifunctional organelles of key importance for cell homeostasis. The outer mitochondrial membrane (OMM) envelops the organelle, and the inner mitochondrial membrane (IMM) is folded into invaginations called cristae. As cristae composition and functions depend on the cell type and stress conditions, they recently started to be considered as a dynamic compartment. A number of proteins are known to play a role in cristae architecture, such as OPA1, MIC60, LETM1, the prohibitin (PHB) complex and the F1FO ATP synthase. Furthermore, phospholipids are involved in the maintenance of cristae ultrastructure and dynamics. The use of new technologies, including super-resolution microscopy to visualize cristae dynamics with superior spatiotemporal resolution, as well as high-content techniques and datasets have not only allowed the identification of new cristae proteins but also helped to explore cristae plasticity. However, a number of open questions remain in the field, such as whether cristae-resident proteins are capable of changing localization within mitochondria, or whether mitochondrial proteins can exit mitochondria through export. In this Review, we present the current view on cristae morphology, stability and composition, and address important outstanding issues that might pave the way to future discoveries.

Keywords:  Cristae; Cristae dynamics; High-content approaches; Mitochondria; Quantitative microscopy

DOI:  https://doi.org/10.1242/jcs.260986
iScience. 2024 Jan 19. 27(1): 108700

Developmental changes of the mitochondria in the murine anteroventral cochlear nucleus.

Anika Hintze, Felix Lange, Anna M Steyer, Jannis Anstatt, Wiebke Möbius, Stefan Jakobs, Carolin Wichmann.

  Mitochondria are key organelles to provide ATP for synaptic transmission. This study aims to unravel the structural adaptation of mitochondria to an increase in presynaptic energy demand and upon the functional impairment of the auditory system. We use the anteroventral cochlear nucleus (AVCN) of wild-type and congenital deaf mice before and after hearing onset as a model system for presynaptic states of lower and higher energy demands. We combine focused ion beam scanning electron microscopy and electron tomography to investigate mitochondrial morphology. We found a larger volume of synaptic boutons and mitochondria after hearing onset with a higher crista membrane density. In deaf animals lacking otoferlin, we observed a shallow increase of mitochondrial volumes toward adulthood in endbulbs, while in wild-type animals mitochondria further enlarged. We propose that in the AVCN, presynaptic mitochondria undergo major structural changes likely to serve higher energy demands upon the onset of hearing and further maturation.

Keywords:  Cell biology; Developmental biology

DOI:  https://doi.org/10.1016/j.isci.2023.108700
bioRxiv. 2023 Dec 23. pii: 2023.12.23.573206. [Epub ahead of print]

Exogenous mitochondrial transfer increases energy expenditure and attenuates adiposity gains in mice with diet-induced obesity.

Maria Namwanje, Soumi Mazumdar, Amanda Stayton, Prisha S Patel, Christine Watkins, Catrina White, Chester Brown, James D Eason, Khyobeni Mozhui, Cem Kuscu, Navjot Pabla, Erin J Stephenson, Amandeep Bajwa.

Obesity is associated with chronic multi-system bioenergetic stress that may be improved by increasing the number of healthy mitochondria available across organ systems. However, treatments capable of increasing mitochondrial content are generally limited to endurance exercise training paradigms, which are not always sustainable long-term, let alone feasible for many patients with obesity. Recent studies have shown that local transfer of exogenous mitochondria from healthy donor tissues can improve bioenergetic outcomes and alleviate the effects of tissue injury in recipients with organ specific disease. Thus, the aim of this project was to determine the feasibility of systemic mitochondrial transfer for improving energy balance regulation in the setting of diet-induced obesity. We found that transplantation of mitochondria from lean mice into mice with diet-induced obesity attenuated adiposity gains by increasing energy expenditure and promoting the mobilization and oxidation of lipids. Additionally, mice that received exogenous mitochondria demonstrated improved glucose uptake, greater insulin responsiveness, and complete reversal of hepatic steatosis. These changes were, in part, driven by adaptations occurring in white adipose tissue. Together, these findings are proof-of-principle that mitochondrial transplantation is an effective therapeutic strategy for limiting the deleterious metabolic effects of diet-induced obesity in mice.

DOI: https://doi.org/10.1101/2023.12.23.573206
J Neurochem. 2024 Jan 09.

Arrestin-3 binds parkin and enhances parkin-dependent mitophagy.

Chen Zheng, Kevin K Nguyen, Sergey A Vishnivetskiy, Vsevolod V Gurevich, Eugenia V Gurevich.

  Arrestins were discovered for their role in homologous desensitization of G-protein-coupled receptors (GPCRs). Later non-visual arrestins were shown to regulate several signaling pathways. Some of these pathways require arrestin binding to GPCRs, the regulation of others is receptor independent. Here, we demonstrate that arrestin-3 binds the E3 ubiquitin ligase parkin via multiple sites, preferentially interacting with its RING0 domain. Identification of the parkin domains involved suggests that arrestin-3 likely relieves parkin autoinhibition and/or stabilizes the enzymatically active "open" conformation of parkin. Arrestin-3 binding enhances ubiquitination by parkin of the mitochondrial protein mitofusin-1 and facilitates parkin-mediated mitophagy in HeLa cells. Furthermore, arrestin-3 and its mutant with enhanced parkin binding rescue mitofusin-1 ubiquitination and mitophagy in the presence of the Parkinson's disease-associated R275W parkin mutant, which is defective in both functions. Thus, modulation of parkin activity via arrestin-3 might be a novel strategy of anti-parkinsonian therapy.

Keywords:  arrestin; mitochondria; mitophagy; parkin

DOI:  https://doi.org/10.1111/jnc.16043
Prog Lipid Res. 2024 Jan 07. pii: S0163-7827(24)00001-8. [Epub ahead of print]94 101268

Mitochondrial phospholipid transport: Role of contact sites and lipid transport proteins.

Vijay Aditya Mavuduru, Lavanya Vadupu, Krishna Kanta Ghosh, Sabyasachi Chakrabortty, Balázs Gulyás, Parasuraman Padmanabhan, Writoban Basu Ball.

  One of the major constituents of mitochondrial membranes is the phospholipids, which play a key role in maintaining the structure and the functions of the mitochondria. However, mitochondria do not synthesize most of the phospholipids in situ, necessitating the presence of phospholipid import pathways. Even for the phospholipids, which are synthesized within the inner mitochondrial membrane (IMM), the phospholipid precursors must be imported from outside the mitochondria. Therefore, the mitochondria heavily rely on the phospholipid transport pathways for its proper functioning. Since, mitochondria are not part of a vesicular trafficking network, the molecular mechanisms of how mitochondria receive its phospholipids remain a relevant question. One of the major ways that hydrophobic phospholipids can cross the aqueous barrier of inter or intraorganellar spaces is by apposing membranes, thereby decreasing the distance of transport, or by being sequestered by lipid transport proteins (LTPs). Therefore, with the discovery of LTPs and membrane contact sites (MCSs), we are beginning to understand the molecular mechanisms of phospholipid transport pathways in the mitochondria. In this review, we will present a brief overview of the recent findings on the molecular architecture and the importance of the MCSs, both the intraorganellar and interorganellar contact sites, in facilitating the mitochondrial phospholipid transport. In addition, we will also discuss the role of LTPs for trafficking phospholipids through the intermembrane space (IMS) of the mitochondria. Mechanistic insights into different phospholipid transport pathways of mitochondria could be exploited to vary the composition of membrane phospholipids and gain a better understanding of their precise role in membrane homeostasis and mitochondrial bioenergetics.

Keywords:  ERMES; Mitochondria; Mitochondrial contact sites; Phospholipid biosynthesis; Phospholipid transport; vCLAMP

DOI:  https://doi.org/10.1016/j.plipres.2024.101268
Biosens Bioelectron. 2024 Jan 02. pii: S0956-5663(24)00003-4. [Epub ahead of print]248 116000

Ratiometric fluorescent biosensor for detection and real-time imaging of nitric oxide in mitochondria of living cells.

Hao Liu, Rou Chen, Kexin Wu, Yuting Zhang, Xiaoli Wang, Nandi Zhou.

  Nitric oxide (NO), a ubiquitous gaseous messenger, plays critical roles in various pathological and physiological progresses. The abnormal levels of NO in organisms are closely related to a large number of maladies. Mitochondria are the main area that produce NO in mammalian cells. Thus, detecting and real-time imaging of NO in mitochondria is of great significance for exploring the biological functions of NO. Herein, a ratiometric fluorescent biosensor (Mito-GNP-pNO520) is developed for sensitive and selective detection and real-time imaging of NO in mitochondria of living cells. The detection is achieved through the fluorescence off-on response of Mito-GNP-pNO520 toward NO. This biosensor shows excellent characteristics, such as high sensitivity toward NO with a low detection limit of 0.25 nM, exclusive selectivity to NO without interference from other substances, good biological stability and low cytotoxicity. More importantly, the biosensor is specifically located in mitochondria, enabling the detection and real-time imaging of endogenous and exogenous NO in mitochondria of living cells. Therefore, our biosensor offers a new approach for dynamic detecting and real-time imaging of NO in subcellular organelles, providing an opportunity to explore new biological effects of NO.

Keywords:  Mitochondrial; Nitric oxide; Quantitative detection; Ratiometric fluorescent biosensor; Real-time imaging

DOI:  https://doi.org/10.1016/j.bios.2024.116000
Cell Mol Life Sci. 2024 Jan 12. 81(1): 26

Emerging roles of mitochondrial functions and epigenetic changes in the modulation of stem cell fate.

Chensong Zhang, Yang Meng, Junhong Han.

  Mitochondria serve as essential organelles that play a key role in regulating stem cell fate. Mitochondrial dysfunction and stem cell exhaustion are two of the nine distinct hallmarks of aging. Emerging research suggests that epigenetic modification of mitochondria-encoded genes and the regulation of epigenetics by mitochondrial metabolites have an impact on stem cell aging or differentiation. Here, we review how key mitochondrial metabolites and behaviors regulate stem cell fate through an epigenetic approach. Gaining insight into how mitochondria regulate stem cell fate will help us manufacture and preserve clinical-grade stem cells under strict quality control standards, contributing to the development of aging-associated organ dysfunction and disease.

Keywords:  Epigenetic modifications; Mitochondria; Mitochondria metabolites; Senescence; Stem cell fate

DOI:  https://doi.org/10.1007/s00018-023-05070-6
iScience. 2024 Jan 19. 27(1): 108702

A mitochondria-targeting dihydroartemisinin derivative as a reactive oxygen species -based immunogenic cell death inducer.

Hong-Yang Zhao, Kun-Heng Li, Dan-Dan Wang, Zhi-Li Zhang, Zi-Jian Xu, Ming-Hui Qi, Shi-Wen Huang.

  Immunogenic cell death (ICD) can activate the anticancer immune response and its occurrence requires high reliance on oxidative stress. Inducing mitochondrial reactive oxygen species (ROS) is a desirable capability for ICD inducers. However, in the category of ICD-associated drugs, numerous reported ICD inducers are a series of anthracyclines and weak in ICD induction. Herein, a mitochondria-targeting dihydroartemisinin derivative (T-D) was synthesized by conjugating triphenylphosphonium (TPP) to dihydroartemisinin (DHA). T-D can selectively accumulate in mitochondria to trigger ROS generation, leading to the loss of mitochondrial membrane potential (ΔΨm) and ER stress. Notably, T-D exhibits far more potent ICD-inducing properties than its parent compound. In vivo, T-D-treated breast cancer cell vaccine inhibits metastasis to the lungs and tumor growth. These results indicate that T-D is an excellent ROS-based ICD inducer with the specific function of trigging vigorous ROS in mitochondria and sets an example for incorporating artemisinin-based drugs into the ICD field.

Keywords:  Cell biology; Immunology; Medical biochemistry

DOI:  https://doi.org/10.1016/j.isci.2023.108702
Nat Metab. 2024 Jan 09.

Paracrine signalling by pancreatic δ cells determines the glycaemic set point in mice.

Jessica L Huang, Mohammad S Pourhosseinzadeh, Sharon Lee, Niels Krämer, Jaresley V Guillen, Naomi H Cinque, Paola Aniceto, Ariana T Momen, Shinichiro Koike, Mark O Huising.

While pancreatic β and α cells are considered the main drivers of blood glucose homeostasis through insulin and glucagon secretion, the contribution of δ cells and somatostatin (SST) secretion to glucose homeostasis remains unresolved. Here we provide a quantitative assessment of the physiological contribution of δ cells to the glycaemic set point in mice. Employing three orthogonal mouse models to remove SST signalling within the pancreas or transplanted islets, we demonstrate that ablating δ cells or SST leads to a sustained decrease in the glycaemic set point. This reduction coincides with a decreased glucose threshold for insulin response from β cells, leading to increased insulin secretion to the same glucose challenge. Our data demonstrate that β cells are sufficient to maintain stable glycaemia and reveal that the physiological role of δ cells is to provide tonic feedback inhibition that reduces the β cell glucose threshold and consequently lowers the glycaemic set point in vivo.

DOI: https://doi.org/10.1038/s42255-023-00944-2
Proc Natl Acad Sci U S A. 2024 Jan 16. 121(3): e2314699121

Local and dynamic regulation of neuronal glycolysis in vivo.

Aaron D Wolfe, John N Koberstein, Chadwick B Smith, Melissa L Stewart, Ian J Gonzalez, Marc Hammarlund, Anthony A Hyman, Philip J S Stork, Richard H Goodman, Daniel A Colón-Ramos.

  Energy metabolism supports neuronal function. While it is well established that changes in energy metabolism underpin brain plasticity and function, less is known about how individual neurons modulate their metabolic states to meet varying energy demands. This is because most approaches used to examine metabolism in living organisms lack the resolution to visualize energy metabolism within individual circuits, cells, or subcellular regions. Here, we adapted a biosensor for glycolysis, HYlight, for use in Caenorhabditis elegans to image dynamic changes in glycolysis within individual neurons and in vivo. We determined that neurons cell-autonomously perform glycolysis and modulate glycolytic states upon energy stress. By examining glycolysis in specific neurons, we documented a neuronal energy landscape comprising three general observations: 1) glycolytic states in neurons are diverse across individual cell types; 2) for a given condition, glycolytic states within individual neurons are reproducible across animals; and 3) for varying conditions of energy stress, glycolytic states are plastic and adapt to energy demands. Through genetic analyses, we uncovered roles for regulatory enzymes and mitochondrial localization in the cellular and subcellular dynamic regulation of glycolysis. Our study demonstrates the use of a single-cell glycolytic biosensor to examine how energy metabolism is distributed across cells and coupled to dynamic states of neuronal function and uncovers unique relationships between neuronal identities and metabolic landscapes in vivo.

Keywords:  C. elegans; biosensor; energy metabolism; glycolysis; neurons

DOI:  https://doi.org/10.1073/pnas.2314699121