bims-tofagi 2026-08-09 papers

Issue of 2026–08–09
five papers selected by
Michele Frison, University of Cambridge

Cell Rep. 2026 Aug 05. pii: S2211-1247(26)00869-7. [Epub ahead of print]45(8): 117791

The coordinated actions of metformin in the intestine and liver improves hyperglycemia.

Ling He, Hongying An, Karina Ramirez, Sally Radovick, Fredric E Wondisford.

Metformin is the first-line oral anti-diabetic agent. Metformin concentrations in the intestine can reach up to 1.3 mM, while those in the portal vein are approximately 0.075 mM. It is unclear whether this metformin concentration difference contributes to metformin's antidiabetic effects. Here, we showed that high metformin concentrations upregulate G6PC expression through AMP-activated protein kinase (AMPK) activation to prevent glucose release in intestinal epithelial cells (IECs). The inhibition of mitochondrial activity by high metformin concentrations leads to drastically increased glucose utilization through glycolysis, along with lactate overproduction in the IECs. Subsequently, glycolytic metabolite lactate is released from IECs into portal vein and delivered to the liver. In the liver, low concentrations of metformin activate AMPK to promote mitochondrial fission and mitophagy to maintain a healthy mitochondrial population, resulting in increased lactate utilization in the mitochondria. These coordinated actions of metformin in the intestine and liver improve hyperglycemia in diabetes and obesity.

Keywords: CP: metabolism; insulin sensitivity; intestine epithelial cells; lactate overproduction; metformin action; mitochondrial respiration

DOI: https://doi.org/10.1016/j.celrep.2026.117791

Science. 2026 Aug 06. 393(6811): 601-606

A molecular switch for coordinating kinesin and dynein transport of mitochondrial cargo.

Christina Gladkova, Maria G Paez-Segala, William P Grant, Mark Kittisopikul, Samuel A Myers, Yuxiao Wang, Ronald D Vale.

The cellular distribution of mitochondria in response to stress and local energy needs is governed by the relative activities of the microtubule-based molecular motors kinesin and dynein. The mechanism for switching between these two opposite-polarity microtubule motors remains unknown. In this study, we coupled a cellular synthetic cargo transport assay with AlphaFold2-guided mutagenesis to identify a regulatory helix in the mitochondrial adaptor protein [trafficking kinesin-binding protein (TRAK)] that mediates switching between kinesin- and dynein-driven transport. Differences in the helix sequence explained why two near-identical TRAK isoforms transported mitochondria in predominantly opposite directions. Phosphorylation of the regulatory helix by stress-activated kinases caused the activation of dynein and dissociation of kinesin. Our results reveal a molecular mechanism for coordinating the directional transport of mitochondria in response to intracellular signals.

DOI: https://doi.org/10.1126/science.aeh1475

Mol Cell. 2026 Aug 06. pii: S1097-2765(26)00463-6. [Epub ahead of print]86(15): 2918-2923

Mitochondria with (distinct) personality.

Won Dong Lee, David J Pagliarini, Zhixing Chen, Aleksandra Trifunovic, Quan Chen, Janine Hertzog Santos, Aleksandra Filipovska, Payam A Gammage.

Cells owe a lot to their mitochondria-to their many mitochondria. Recent discoveries and emerging technologies point to functional distinctions within that population. We asked a group of researchers about what mitochondrial heterogeneity means for understanding cellular and organismal physiology.

DOI: https://doi.org/10.1016/j.molcel.2026.06.044

Free Radic Biol Med. 2026 Aug 03. pii: S0891-5849(26)00985-8. [Epub ahead of print]255 573-590

Crosstalk between mitophagy and metabolism in cancer: Mechanisms and therapeutic opportunities.

Jingyi Cheng, Ting Xiao, Zhangui Tang, Yuhan Chen.

Mitophagy is a highly selective autophagic process that eliminates dysfunctional mitochondria to enforce stringent cellular quality control, acting as a context-dependent modulator of stress adaptation in cancer cells. Concurrently, to thrive in hostile microenvironments, cancer cells undergo extensive metabolic reprogramming to fulfill the immense bioenergetic and anabolic demands of rapid proliferation. Rather than operating independently, mitophagy and metabolism are intrinsically coupled to form a highly sophisticated and bidirectional regulatory circuit. Metabolic disturbances trigger mitophagy, while mitophagy reciprocally remodels metabolic landscape. This crosstalk functions as a critical metabolic rheostat, equipping cancer cells with the dynamic plasticity required to cope with the dynamic physicochemical stresses. Furthermore, this mitophagy-metabolism crosstalk extends beyond cancer cells into the tumor microenvironment, orchestrating systemic metabolic symbiosis and driving immune evasion. In this review, we summarize the molecular mechanisms underpinning this crosstalk, and highlight how therapeutic targeting of these vulnerabilities offer opportunities for overcoming therapeutic resistance and improving clinical outcomes.

Keywords: Cancer; Metabolic reprogramming; Mitophagy; Tumor microenvironment

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.08.004

Autophagy. 2026 Aug 06. 1-17

Molecular switches of SQSTM1: the impact of post-translational modifications on autophagy and neurodegeneration.

F Abrar, D D O Martin.

SQSTM1/p62 (sequestosome 1) is an important receptor protein involved in many cellular signaling processes, including macroautophagy/autophagy. It is a molecular hub for cellular homeostasis and cellular responses. Within autophagy, SQSTM1 targets ubiquitinated cargo for degradation, maintaining cellular proteostasis. Structurally, SQSTM1 consists of several domains that facilitate its binding to ubiquitinated cargo, the formation of SQSTM1 aggregate inclusions, interactions with MAP1LC3/LC3, and the mediation of clearance via the autophagy pathway. Beyond its structure, post-translational modifications of SQSTM1 dynamically regulate its function within a cell. Post-translational modifications - such as phosphorylation, ubiquitination, acetylation, S-acylation, and S-nitrosylation - are crucial for regulating SQSTM1 function, localization, and interaction with autophagic components, thereby influencing SQSTM1's role in the autophagy pathway. Understanding the role of these protein modifications in modulating autophagy may provide better insight into developing therapeutic strategies for diseases with dysregulated autophagy, such as neurodegenerative diseases. This review will discuss the role of these post-translational modifications in controlling SQSTM1's localization and function in autophagy.Abbreviations: ABHD = α/β-hydrolase domain; AD = Alzheimer Disease; ALS = amyotrophic lateral sclerosis; ATG = autophagy related ; CSNK2/CK2 = casein kinase 2; HD = Huntington Disease; HDAC/KDAC = histone deacetylase/lysine deacetylase; HTT = huntingtin; KAT = lysine acetyltransferase; KEAP1 = kelch like ECH associated protein 1; KIR = KEAP1-interacting region; LIR = LC3-interacting region; LYPLA/APT = lysophospholipase/acyl-protein thioesterase; MAP1LC3/LC3 = microtubule associated protein 1 light chain 3; MEF = mouse embryonic fibroblast; mHTT = mutant huntingtin; MTORC1 = MTOR complex 1; NBR1 = NBR1 autophagy cargo receptor; NEDD4 = NEDD4 E3 ubiquitin protein ligase ; NO = nitric oxide; NFE2L2/Nrf2 = nuclear factor erythroid 2-factor 2; PAT = palmitoyl acyltransferase; PB1 = Phox-BEM1 domain; PE = phosphatidylethanolamine; PLEKHM1 = pleckstrin homology and RUN domain containing M1; PLK2 = polo like kinase 2; PRKA/PKA = protein kinase cAMP-activated; PPT1 = palmitoyl-protein thioesterase 1; RB1CC1 = RB1 inducible coiled-coil 1; SNCA/α-synuclein = synuclein alpha; SNO = S-nitrosothiol; SOD1 = superoxide dismutase 1; SQSTM1 = sequestosome 1; TARDBP/TDP-43 = TAR DNA binding protein ; TBK1 = TANK binding kinase 1; TAX1BP1 = Tax1 binding protein 1; TRIM = tripartite motif containing ; UBA = ubiquitin-associated domain; UBE = ubiquitin-conjugating enzyme; ULK1 = unc-51 like autophagy activating kinase 1; UPS =ubiquitin-proteasome system; USP8 = ubiquitin specific peptidase 8; ZDHHC = zDHHC palmitoyltransferase.

Keywords: Neuroscience; S-acylation; p62; post-translational modifications; sequestosome 1

DOI: https://doi.org/10.1080/15548627.2026.2711593