bims-mitdyn 2025-01-12 papers

Nat Commun. 2025 Jan 07. 16(1): 451

Mitochondria- and ER-associated actin are required for mitochondrial fusion.

Priya Gatti, Cara Schiavon, Julien Cicero, Uri Manor, Marc Germain.

Mitochondria are crucial for cellular metabolism and signalling. Mitochondrial activity is modulated by mitochondrial fission and fusion, which are required to properly balance metabolic functions, transfer material between mitochondria, and remove defective mitochondria. Mitochondrial fission occurs at mitochondria-endoplasmic reticulum (ER) contact sites, and requires the formation of actin filaments that drive mitochondrial constriction and the recruitment of the fission protein DRP1. The role of actin in mitochondrial fusion remains entirely unexplored. Here we show that preventing actin polymerisation on either mitochondria or the ER disrupts both fission and fusion. We show that fusion but not fission is dependent on Arp2/3, whereas both fission and fusion require INF2 formin-dependent actin polymerization. We also show that mitochondria-associated actin marks fusion sites prior to the fusion protein MFN2. Together, our work introduces a method for perturbing organelle-associated actin and demonstrates a previously unknown role for actin in mitochondrial fusion.

DOI: https://doi.org/10.1038/s41467-024-55758-x

Mitochondrion. 2025 Jan 07. pii: S1567-7249(25)00003-0. [Epub ahead of print] 102006

Yeast Dnm1G178R causes altered organelle dynamics and sheds light on the human DRP1G149R disease mechanism.

Ankita Adhikary, Vivian Francis Joseph, Riddhi Banerjee, Shirisha Nagotu.

Mitochondrial morphology is a result of regulated opposite events called fission and fusion and requires the GTPase, dynamin-related protein 1 (DRP1/Dnm1), or its homologs. A recent clinical report identified a heterozygous missense mutation in the human DRP1 that replaces Glycine (G) 149 with Arginine (R) and results in debilitating conditions in the patient. In this study, we mimicked this mutation in yeast Dnm1 (G178R) and investigated the impact of the pathogenic mutation on the protein's function. We provide evidence that the substitution of G with R in the G3 motif of the GTPase domain, renders the protein non-functional and in a dominant-negative way. The mutation hampers the distribution, localization, and function of the protein. Cells expressing the mutant variant are blocked in mitochondrial fission and exhibit altered peroxisome morphology and number.

Keywords: Dynamin-related protein 1; Mitochondria; Mutations; Peroxisome; Yeast

DOI: https://doi.org/10.1016/j.mito.2025.102006

SLAS Discov. 2025 Jan 06. pii: S2472-5552(25)00001-2. [Epub ahead of print] 100208

Novel high-content and open-source image analysis tools for profiling mitochondrial morphology in neurological cell models.

Marcus Y Chin, David A Joy, Madhuja Samaddar, Anil Rana, Johann Chow, Takashi Miyamoto, Meredith Calvert.

Mitochondria undergo dynamic morphological changes depending on cellular cues, stress, genetic factors, or disease. The structural complexity and disease-relevance of mitochondria have stimulated efforts to generate image analysis tools for describing mitochondrial morphology for therapeutic development. Using high-content analysis, we measured multiple morphological parameters and employed unbiased feature clustering to identify the most robust pair of texture metrics that described mitochondrial state. Here, we introduce a novel image analysis pipeline to enable rapid and accurate profiling of mitochondrial morphology in various cell types and pharmacological perturbations. We applied a high-content adapted implementation of our tool, MitoProfilerHC, to quantify mitochondrial morphology changes in i) a mammalian cell dose response study and ii) compartment-specific drug effects in primary neurons. Next, we expanded the usability of our pipeline by using napari, a Python-powered image analysis tool, to build an open-source version of MitoProfiler and validated its performance and applicability. In conclusion, we introduce MitoProfiler as both a high-content-based and an open-source method to accurately quantify mitochondrial morphology in cells, which we anticipate to greatly facilitate mechanistic discoveries in mitochondrial biology and disease.

Keywords: Mitochondria; high-content imaging; high-throughput screening; image analysis; mitochondrial morphology; napari plugin; neurons; open-source

DOI: https://doi.org/10.1016/j.slasd.2025.100208

Curr Alzheimer Res. 2025 Jan 08.

Mitochondrial Fragmentation as a Key Driver of Neurodegenerative Disease.

Alina Chaplygina, Daria Zhdanova.

Mitochondrial form and function are intricately linked through dynamic processes of fusion and fission, and disruptions in these processes are key drivers of neurodegenerative diseases, like Alzheimer's. The inability of mitochondria to transition between their dynamic forms is a critical factor in the development of pathological states. In this paper, we focus on the importance of different types of mitochondrial phenotypes in nervous tissue, discussing how mitochondria in Alzheimer's disease are "stuck" in certain patterns and how this pattern maintains itself. Understanding the specific roles and transitions between mitochondrial forms, including tiny, networked, and hyperfused, is crucial in developing new therapies aimed at restoring mitochondrial homeostasis. By targeting these dynamics, we may be able to intervene early in the disease process, offering novel avenues for preventing or treating neurodegeneration.

Keywords: Alzheimer's disease.; Mitochondria; fission; fusion; mitochondrial phenotypes; mitophagy

DOI: https://doi.org/10.2174/0115672050366194250107050650

Int J Mol Sci. 2024 Dec 22. pii: 13714. [Epub ahead of print]25(24):

Sexual Dimorphism of Ethanol-Induced Mitochondrial Dynamics in Purkinje Cells.

Rehana Khatoon, Jordan Fick, Abosede Elesinnla, Jaylyn Waddell, Tibor Kristian.

The cerebellum, a key target of ethanol's toxic effects, is associated with ataxia following alcohol consumption. However, the impact of ethanol on Purkinje cell (PC) mitochondria remains unclear. To investigate how ethanol administration affects mitochondrial dynamics in cerebellar Purkinje cells, we employed a transgenic mouse model expressing mitochondria-targeted yellow fluorescent protein in Purkinje cells (PC-mito-eYFP). Both male and female PC-mito-eYFP mice received an intraperitoneal injection of ethanol or vehicle. One hour after ethanol administration, the animals were perfusion fixed or their cerebellum tissue or isolated mitochondria were collected. Cerebellum sections were analyzed using confocal microscopy to assess changes in mitochondrial length distribution. In vivo superoxide levels were measured using dihydroethidium (DHE), and mitochondrial NAD levels were determined by high-performance liquid chromatography (HPLC). Our findings revealed a sex-dependent response to ethanol administration in mitochondrial size distribution. While male Purkinje cell mitochondria exhibited no significant changes in size, female mitochondria became more fragmented after one hour of ethanol administration. This coincided with elevated phosphorylation of the fission protein Drp1 and increased superoxide production, as measured by DHE fluorescence intensity. Similarly, mitochondrial NAD levels were significantly reduced in female mice, but no changes were observed in males. Our results demonstrate that ethanol induced mitochondrial fragmentation through increased free radical levels, due to reduced NAD and increased p-Drp1, in PC cells of the female cerebellum.

Keywords: Purkinje cells; alcohol; cerebellum; free radicals; mitochondria

DOI: https://doi.org/10.3390/ijms252413714