bims-tofagi 2024-12-01 papers

Issue of 2024–12–01
five papers selected by
Michele Frison, University of Cambridge

Cell Rep. 2024 Nov 23. pii: S2211-1247(24)01352-4. [Epub ahead of print]43(12): 115001

AMPK regulates Bcl2-L-13-mediated mitophagy induction for cardioprotection.

Tomokazu Murakawa, Jumpei Ito, Mara-Camelia Rusu, Manabu Taneike, Shigemiki Omiya, Javier Moncayo-Arlandi, Chiaki Nakanishi, Ryuta Sugihara, Hiroki Nishida, Kentaro Mine, Roland Fleck, Min Zhang, Kazuhiko Nishida, Ajay M Shah, Osamu Yamaguchi, Yasushi Sakata, Kinya Otsu.

The accumulation of damaged mitochondria in the heart is associated with heart failure. Mitophagy is an autophagic degradation system that specifically targets damaged mitochondria. We have reported previously that Bcl2-like protein 13 (Bcl2-L-13) mediates mitophagy and mitochondrial fission in mammalian cells. However, the in vivo function of Bcl2-L-13 remains unclear. Here, we demonstrate that Bcl2-L-13-deficient mice and knockin mice, in which the phosphorylation site (Ser272) on Bcl2-L-13 was changed to Ala, showed left ventricular dysfunction in response to pressure overload. Attenuation of mitochondrial fission and mitophagy led to impairment of ATP production in these mouse hearts. In addition, we identified AMPKα2 as the kinase responsible for the phosphorylation of Bcl2-L-13 at Ser272. These results indicate that Bcl2-L-13 and its phosphorylation play an important role in maintaining cardiac function. Furthermore, the amplitude of stress-stimulated mitophagic activity could be modulated by AMPKα2.

Keywords: Bcl2-L-13; CP: Cell biology; heart failure; mitochondria; mitophagy

DOI: https://doi.org/10.1016/j.celrep.2024.115001

Glia. 2024 Nov 27.

Modulation of OPC Mitochondrial Function by Inhibiting USP30 Promotes Their Differentiation.

Allison L Soung, Roxanne V Kyauk, Shristi Pandey, Yun-An A Shen, Mike Reichelt, Han Lin, Zhiyu Jiang, Praveen Kirshnamoorthy, Oded Foreman, Benjamin E Lauffer, Tracy J Yuen.

Multiple lines of evidence indicate that mitochondrial dysfunction occurs in demyelinating diseases, such as multiple sclerosis (MS). Failure of remyelination is thought to be caused in part by a block of oligodendrocyte progenitor cell (OPC) differentiation into oligodendrocytes, which generate myelin sheaths around axons. The process of OPC differentiation requires a substantial amount of energy and high demand for ATP which is supplied through the mitochondria. In this study, we highlight mitochondrial gene expression changes during OPC differentiation in two murine models of remyelination and in human postmortem MS brains. Given these transcriptional alterations, we then investigate whether genetic alteration of USP30, a mitochondrial deubiquitinase, enhances OPC differentiation and myelination. By genetic knockout of USP30, we observe increased OPC differentiation and myelination without affecting OPC proliferation and survival in in vitro and ex vivo assays. We also find that OPC differentiation is accelerated in vivo following focal demyelination in USP30 knockout mice. The promotion of OPC differentiation and myelination observed is associated with increased oxygen consumption rates in USP30 knockout OPCs. Together, these data indicate a role for mitochondrial function and USP30 in OPC differentiation and myelination.

Keywords: USP30; demyelination; mitochondria; myelination; oligodendrocytes; remyelination

DOI: https://doi.org/10.1002/glia.24648

Front Neurosci. 2024 ;18 1496142

Mutations in mitochondrial ATAD3 gene and disease, lessons from in vivo models.

Marcel Brügel, Ann-Sophie Kiesel, Tobias B Haack, Susana Peralta.

Pathogenic variants in the ATAD3 gene cluster have been associated with different neurodevelopmental disorders showing clinical symptoms like global developmental delay, muscular hypotonia, cardiomyopathy, congenital cataracts, and cerebellar atrophy. ATAD3A encodes for a mitochondrial ATPase whose function is unclear and has been considered one of the five most common nuclear genes associated with mitochondrial diseases in childhood. However, the mechanism causing ATAD3-associated disorders is still unknown. In vivo models have been used to identify ATAD3 function. Here we summarize the features of mouse models with ATAD3 loss of function and Drosophila models overexpressing pathogenic ATAD3 variants. We discuss how these models have contributed to our understanding of ATAD3 function and the pathomechanism of the ATAD3-associated disease.

Keywords: ATAD3; animal model; cholesterol; mitochondrial disease; mtDNA depletion and deletion; neurodegeneration

DOI: https://doi.org/10.3389/fnins.2024.1496142

Antioxidants (Basel). 2024 Nov 01. pii: 1343. [Epub ahead of print]13(11):

Mitochondrial Quality Control in Alzheimer's Disease: Insights from Caenorhabditis elegans Models.

Upasana Ganguly, Trae Carroll, Keith Nehrke, Gail V W Johnson.

Alzheimer's disease (AD) is a complex neurodegenerative disorder that is classically defined by the extracellular deposition of senile plaques rich in amyloid-beta (Aβ) protein and the intracellular accumulation of neurofibrillary tangles (NFTs) that are rich in aberrantly modified tau protein. In addition to aggregative and proteostatic abnormalities, neurons affected by AD also frequently possess dysfunctional mitochondria and disrupted mitochondrial maintenance, such as the inability to eliminate damaged mitochondria via mitophagy. Decades have been spent interrogating the etiopathogenesis of AD, and contributions from model organism research have aided in developing a more fundamental understanding of molecular dysfunction caused by Aβ and toxic tau aggregates. The soil nematode C. elegans is a genetic model organism that has been widely used for interrogating neurodegenerative mechanisms including AD. In this review, we discuss the advantages and limitations of the many C. elegans AD models, with a special focus and discussion on how mitochondrial quality control pathways (namely mitophagy) may contribute to AD development. We also summarize evidence on how targeting mitophagy has been therapeutically beneficial in AD. Lastly, we delineate possible mechanisms that can work alone or in concert to ultimately lead to mitophagy impairment in neurons and may contribute to AD etiopathology.

Keywords: Alzheimer’s disease; Caenorhabditis elegans; aging; mitochondria; mitochondria quality control; mitophagy; model organism; neurodegeneration

DOI: https://doi.org/10.3390/antiox13111343