bims-mitdyn 2023-02-05 papers

Issue of 2023‒02‒05
five papers selected by
Edmond Chan
Queen’s University, School of Medicine

PNAS Nexus. 2022 Sep;1(4): pgac192

An explanation of how mutant and wild-type mitochondria might stably co-exist in inherited mitochondrial diseases.

Axel Kowald, Felix P Kemeth, Tom B L Kirkwood.

Mitochondria are cellular organelles of crucial relevance for the survival of metazoan organisms. Damage to the mitochondrial DNA can give rise to a variety of mitochondrial diseases and is thought also to be involved in the aging process. The fate of mtDNA mutants is controlled by their synthesis as well as degradation and mathematical models can help to better understand this complex interplay. We present here a model that combines a replicative advantage for mtDNA mutants with selective degradation enabled by mitochondrial fission and fusion processes. The model not only shows that the cell has efficient means to deal with (many) types of mutants but, surprisingly, also predicts that under certain conditions a stable co-existence of mutant and wild-type mtDNAs is possible. We discuss how this new finding might explain how mitochondria can be at the heart of processes with such different phenotypes as mitochondrial diseases and aging.

Keywords: aging; mathematical model; mitochondrial disease

DOI: https://doi.org/10.1093/pnasnexus/pgac192

Cell Rep. 2023 Jan 30. pii: S2211-1247(23)00044-X. [Epub ahead of print]42(2): 112033

Numb/Parkin-directed mitochondrial fitness governs cancer cell fate via metabolic regulation of histone lactylation.

Cell plasticity and neuroendocrine differentiation in prostate and lung adenocarcinomas are one of the major reasons for therapeutic resistance to targeted therapy. Whether and how metabolic changes contribute to this adenocarcinoma-to-neuroendocrine cell fate transition remains largely unclear. Here we show that neuroendocrine prostate or lung cancer cells possess mostly fragmented mitochondria with low membrane potential and rely on glycolysis for energy metabolism. We further show an important role of the cell fate determinant Numb in mitochondrial quality control via binding to Parkin and facilitating Parkin-mediated mitophagy. Deficiency in the Numb/Parkin pathway in prostate or lung adenocarcinomas causes a metabolic reprogramming featured with a significant increase in production of lactate acid, which subsequently leads to an upregulation of histone lactylation and transcription of neuroendocrine-associated genes. Collectively, the Numb/Parkin-directed mitochondrial fitness is a key metabolic switch and a promising therapeutic target on cancer cell plasticity through the regulation of histone lactylation.

Keywords: CP: Cancer; CP: Metabolism; Numb; Parkin; cell fate plasticity; mitochondrial quality control; neuroendocrine differentiation; prostate cancer

DOI: https://doi.org/10.1016/j.celrep.2023.112033

Elife. 2023 Feb 01. pii: e82283. [Epub ahead of print]12

A mouse model of human mitofusin 2-related lipodystrophy exhibits adipose-specific mitochondrial stress and reduced leptin secretion.

Jake P Mann, Xiaowen Duan, Satish Patel, Luis Carlos Tábara, Fabio Scurria, Anna Alvarez-Guaita, Afreen Haider, Ineke Luijten, Matthew Page, Margherita Protasoni, Koini Lim, Sam Virtue, Stephen O'Rahilly, Martin Armstrong, Julien Prudent, Robert K Semple, David B Savage.

Mitochondrial dysfunction has been reported in obesity and insulin resistance, but primary genetic mitochondrial dysfunction is generally not associated with these, arguing against a straightforward causal relationship. A rare exception, recently identified in humans, is a syndrome of lower body adipose loss, leptin-deficient severe upper body adipose overgrowth, and insulin resistance caused by the p.Arg707Trp mutation in MFN2, encoding mitofusin 2. How the resulting selective form of mitochondrial dysfunction leads to tissue- and adipose depot-specific growth abnormalities and systemic biochemical perturbation is unknown. To address this, Mfn2R707W/R707W knock-in mice were generated and phenotyped on chow and high fat diets. Electron microscopy revealed adipose-specific mitochondrial morphological abnormalities. Oxidative phosphorylation measured in isolated mitochondria was unperturbed, but the cellular integrated stress response was activated in adipose tissue. Fat mass and distribution, body weight, and systemic glucose and lipid metabolism were unchanged, however serum leptin and adiponectin concentrations, and their secretion from adipose explants were reduced. Pharmacological induction of the integrated stress response in wild-type adipocytes also reduced secretion of leptin and adiponectin, suggesting an explanation for the in vivo findings. These data suggest that the p.Arg707Trp MFN2 mutation selectively perturbs mitochondrial morphology and activates the integrated stress response in adipose tissue. In mice, this does not disrupt most adipocyte functions or systemic metabolism, whereas in humans it is associated with pathological adipose remodelling and metabolic disease. In both species, disproportionate effects on leptin secretion may relate to cell autonomous induction of the integrated stress response.

Keywords: cell biology; mouse

DOI: https://doi.org/10.7554/eLife.82283

Bioessays. 2023 Jan 29. e2200160

Mitochondrial protein import machinery conveys stress signals to the cytosol and beyond.

Eirini Lionaki, Ilias Gkikas, Nektarios Tavernarakis.

Mitochondria hold diverse and pivotal roles in fundamental processes that govern cell survival, differentiation, and death, in addition to organismal growth, maintenance, and aging. The mitochondrial protein import system is a major contributor to mitochondrial biogenesis and lies at the crossroads between mitochondrial and cellular homeostasis. Recent findings highlight the mitochondrial protein import system as a signaling hub, receiving inputs from other cellular compartments and adjusting its function accordingly. Impairment of protein import, in a physiological, or disease context, elicits adaptive responses inside and outside mitochondria. In this review, we discuss recent developments, relevant to the mechanisms of mitochondrial protein import regulation, with a particular focus on quality control, proteostatic and metabolic cellular responses, triggered upon impairment of mitochondrial protein import.

Keywords: metabolism; mitochondrial protein import; mitochondrial unfolded protein response; mitophagy; proteostasis

DOI: https://doi.org/10.1002/bies.202200160

Endocr Rev. 2023 Feb 02. pii: bnad004. [Epub ahead of print]

Intra-cellular to inter-organ mitochondrial communication in striated muscle in health and disease.

Neoma T Boardman, Giulia Trani, Marco Scalabrin, Vanina Romanello, Rob C I Wüst.

Mitochondria both sense biochemical and energetic input in addition to communicating signals regarding the energetic state of the cell. Increasingly, these signaling organelles are key for regulating different cell functions. This review summarizes recent advances in mitochondrial communication in striated muscle, with specific focus on the processes by which mitochondria communicate with each other, other organelles and across distant organ systems. Inter-mitochondrial communication in striated muscle is mediated via conduction of the mitochondrial membrane potential to adjacent mitochondria, physical interactions, mitochondrial fusion or fission and via nannotunnels, allowing for the exchange of proteins, mitochondrial DNA, nucleotides, and peptides. Within striated muscle cells, mitochondria-organelle communication can modulate overall cell function. The various mechanisms in which mitochondria communicate mitochondrial fitness to the rest of the body suggest that extracellular mitochondrial signaling is key during health and disease. Whereas mitochondrial-derived vesicles might excrete mitochondrial-derived endocrine compounds, stimulation of mitochondrial stress can lead to the release of fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) into the circulation to modulate whole-body physiology. Circulating mitochondrial DNA are well-known alarmins that trigger the immune system and may help to explain low-grade inflammation in various chronic diseases. Impaired mitochondrial function and communication are central in common heart and skeletal muscle pathologies, including cardiomyopathies, insulin resistance, and sarcopenia. Lastly, important new advances in research in mitochondrial endocrinology, communication, medical horizons and translational aspects are discussed.

Keywords: FGF21; GDF15; mitochondria-organelle interactions; mitochondrial cristae; mitochondrial dynamics; myokines; respiratory supercomplexes

DOI: https://doi.org/10.1210/endrev/bnad004