bims-mithem 2026-03-15 papers

Issue of 2026–03–15
five papers selected by
Tim van Tienhoven, Erasmus Medical Center

Mech Ageing Dev. 2026 Mar 05. pii: S0047-6374(26)00019-9. [Epub ahead of print]231 112167

Mitochondrial quality in aging and neurodegeneration: The emerging role of mitochondria-derived vesicles.

Emanuele Marzetti, Rosa Di Lorenzo, Riccardo Calvani, Hélio José Coelho-Júnior, Ettore D'Argento, Vito Pesce, Francesco Landi, Cecilia Bucci, Flora Guerra, Anna Picca.

Mitochondria are central to cellular energy metabolism, redox balance, and signaling, and their integrity is maintained by a multilayered mitochondrial quality control (MQC) system. This system includes proteostasis, dynamics, biogenesis, and mitophagy, which together repair or remove damaged organelles. Mitochondria-derived vesicles (MDVs) have emerged as an additional MQC component. MDVs are small vesicles that bud from mitochondria and selectively transport damaged mitochondrial proteins, lipids, and nucleic acids to endolysosomal compartments or other intracellular destinations, enabling rapid and localized responses to mitochondrial stress. Acting upstream of or in parallel with mitophagy, MDVs can avoid or delay irreversible mitochondrial damage and help preserve cellular homeostasis. Aging and age-associated disorders are characterized by progressive mitochondrial dysfunction and chronic inflammation. Age-related changes in intracellular trafficking, lysosomal function, and vesicle dynamics may impair MDV formation, cargo selection, and targeting. Under conditions of defective degradation, mitochondrial components may also appear in extracellular vesicles, potentially contributing to altered intercellular signaling and inflammation. In the nervous system, where energetic demands are high and mitochondrial turnover requires tight regulation, such alterations may be especially harmful. This review summarizes MQC mechanisms in neurons, with a focus on MDVs, their dysregulation during aging and neurodegeneration, and implications for biomarkers and therapeutic strategies.

Keywords: Alzheimer’s disease; Huntington’s disease; Parkinson’s disease; Tau protein, α-synuclein

DOI: https://doi.org/10.1016/j.mad.2026.112167

BMB Rep. 2026 Mar 09. pii: 6743. [Epub ahead of print]

Mitochondrial Quantity-Quality Imbalance in Cellular Senescence: Practical Readouts and Minimal Assay Bundles.

Myeongwoo Jung, Seongho Cha, Eun Kyung Lee.

Cellular senescence is an irreversible program of cell-cycle arrest that accumulates with age, contributing to chronic inflammation and various age-related diseases. A key feature of senescence paradigms is mitochondrial dysfunction, which involves not just a single defect but a series of coordinated changes in bioenergetics, redox homeostasis, mitochondrial quality control, and organelle interaction. Senescent cells often display a "quantity-quality imbalance" in their mitochondria: while the mitochondrial mass may increase, their efficiency in oxidative phosphorylation decreases, leading to a destabilized membrane potential (ΔΨm) and elevated levels of mitochondrial reactive oxygen species (mtROS). These interrelated changes can exacerbate senescence through persistent stress signaling, impaired turnover of damaged mitochondrial components, and alterations in organelle contacts, such as those between endoplasmic reticulum (ER) and mitochondria, and between mitochondria and lysosomes. Given that these phenotypes differ depending on cell type, triggering factors, and timing, no single assay can adequately define senescence-associated mitochondrial dysfunction. In this review, we present practical, complementary strategies that include extracellular flux-based respiration profiling, ATP output measurement, ΔΨm and ROS assessments, flux-based mitophagy reporters, quantitative network imaging, and contact-site assays. We propose minimal assay bundles that allow for a thorough multidimensional analysis. By establishing standardized, orthogonal measures of mitochondrial quantity and quality, we aim to enhance mechanistic understanding and facilitate the rational evaluation of mitochondria-targeted senolytic and senomorphic therapies.

iScience. 2026 Mar 20. 29(3): 114921

Metabolic and epigenetic interplay in HSPC specification: A balance between extrinsic and intrinsic cues.

Maria Kalogeraki, Vincent Rondeau, Zeina Abou Nader, Marion Espéli, Karl Balabanian.

Hematopoietic stem and progenitor cells (HSPCs), including multipotent progenitors (MPPs), sustain lifelong blood production by integrating intrinsic metabolic and epigenetic mechanisms with extrinsic cues from the bone marrow (BM) niche. Epigenetic mechanisms interact with metabolic pathways to establish a coordinated network that supports HSPC maintenance and differentiation. Spatially defined signals within BM niches shape HSPC metabolic and epigenetic states and govern lineage specification. Herein, we review recent advances on the bidirectional relationship between metabolism and epigenetics in HSPCs, emphasizing how both intrinsic and niche-derived factors regulate fate decisions under steady-state and pathological conditions. Particular attention is given to the CXCL12/CXCR4 signaling axis, a central regulator of HSPC retention, migration, and quiescence, and its emerging role in orchestrating metabolic and epigenetic mechanisms. Integrating intrinsic regulatory networks with dynamic extrinsic signals provide a conceptual framework for understanding HSPC fate and may uncover strategies for regenerative medicine and hematological disease therapy.

Keywords: biological sciences; cell biology; molecular biology

DOI: https://doi.org/10.1016/j.isci.2026.114921

Nat Genet. 2026 Mar;58(3): 582-592

CDK4/6 inhibition mitigates chemotherapy-induced expansion of TP53-mutant clonal hematopoiesis.

Irenaeus C C Chan, Pu Zhang, Xiangyu Pan, Cynthia Castro, Nina Fox, Alexander M Lewis, Kenyon Weis, Adriana Cuibus, Steven Tittley, Giulia Petrone, J Scott Beeler, Duc Tran, Griffen Mustion, Catrina Fronick, Konrad H Stopsack, Carlos Cruchaga, Omar Abdel-Wahab, Kelly L Bolton.

Therapy-related myeloid neoplasm (tMN) is a fatal consequence of exposure to cytotoxic therapy administered in the treatment of cancer. Individuals with pre-existing TP53 clonal hematopoiesis (CH) are at high risk of tMN, with avoidance of therapy being the only strategy to reduce tMN risk. Here, in four randomized clinical trials, we show that the CDK4/6 inhibitor trilaciclib, given in conjunction with a variety of chemotherapeutic regimens and across diverse populations of patients with cancer, mitigates chemotherapy-related expansion of CH clones with mutations in DNA damage response genes, including TP53. This finding was also observed in a syngeneic mouse model of TP53-mutant CH, demonstrating that CDK4/6 inhibition blocks platinum-induced TP53 competitive repopulation through promoting hematopoietic stem and progenitor quiescence and decreasing the stemness advantage of TP53-mutant clones. This represents a proof of concept for a potential pharmacologic strategy to block chemotherapy-induced expansion of preleukemic TP53-mutant clones.

DOI: https://doi.org/10.1038/s41588-026-02526-w

Cell Rep Med. 2026 Mar 10. pii: S2666-3791(26)00080-7. [Epub ahead of print] 102663

Detection of mitochondrial DNA mutations in T cells following 5-FU or cisplatin exposure.

Catherine Kirkpatrick, Charles M Quick, Steven R Post, Yuet-Kin Leung, Ruud P M Dings, Chrystal M Paulos, Lyle Burdine, Yong-Chen William Lu.

T cells are pivotal to cancer immunotherapy, yet chemotherapy may erode their fitness. Using a single-cell technique, we show that exposure to two widely used chemotherapeutic agents, 5-FU (5-fluorouracil) and cisplatin, induces non-synonymous mitochondrial DNA (mtDNA) mutations in T cells. Notably, nearly all detected mtDNA mutations are transition mutations. Like the effects observed in genomic DNA mutations, the impacts of mtDNA mutations in T cells appear to be random. Some T cells with mtDNA mutations concentrate in clusters associated with gene markers, while others do not. Additionally, several mtDNA mutations are found in the fraction of treated T cells with low mitochondrial activity, suggesting their potential effect on mitochondrial function. Importantly, mtDNA mutations are detected in tumor-infiltrating T cells from patients with colorectal cancer who received chemotherapy. Our findings uncover an unappreciated consequence of chemotherapy on T cell mitochondria, and these results raise concerns about administering immunotherapy and chemotherapy concurrently.

Keywords: T cell biology; cancer immunotherapy; combination therapy; mitochondrial biology; single-cell genomics

DOI: https://doi.org/10.1016/j.xcrm.2026.102663