A grafting-rescued albino mutant reveals the essential function of CspTAC12 in cucumber chloroplast biogenesis.

Environmental stress-induced mitochondrial metabolic reprogramming as a central driver of endocrine dysfunction: A food and chemical toxicology perspective.

Plastid-to-nucleus retrograde signaling coordinates nuclear gene expression with the developmental and physiological state of plastids. GENOMES UNCOUPLED 1 (GUN1), a chloroplast-localized PPR-SMR protein, remains a central yet poorly understood component of this network. Its low abundance, rapid turnover and conditional phenotypes challenge functional interpretation. GUN1 has been proposed as a hub integrating stress responses, tetrapyrrole synthesis and protein homeostasis, with downstream effects mediated by factors, such as ABI4, but many of these claims are challenged by recent evidence. Here, we identify claims that have failed to replicate, highlight established consensus and outline a path toward a more grounded understanding of GUN1. Beyond its confirmed RNA-binding activity, GUN1 may act as a moonlighting checkpoint, modulating when plastid dysfunction triggers nuclear and developmental responses.

Protein homeostasis is critical for mitochondrial function and is maintained by proteases and chaperones that respond to stress and mediate adaptive changes such as the mitochondrial unfolded protein response (UPRmt), the integrated stress response (ISR) and antioxidant signaling. However, the mechanisms by which stressors regulate these retrograde responses remains uncharacterized in muscle. Thus, we examined the effect of mitochondrial stressors on the activation of these pathways in myoblasts and differentiated myotubes. Cells were exposed to either 1) CDDO, a LonP1 protease inhibitor, 2) GTPP, an HSP90 chaperone inhibitor, 3) CCCP, an energetic uncoupler, or 4) MB-10, an inhibitor of protein import, and responses were compared to those induced by acute contractile activity (ACA). LonP1 inhibition activated ATF4 and Nrf2 signaling, increased mitochondrial chaperones, and resulted in protein aggregation without elevating reactive oxygen species (ROS). In contrast, blocking HSP90 led to increases in mitochondrial ROS and activation of CHOP, indicating protein homeostasis-related stress with limited antioxidant signaling. ACA elicited responses similar to the inhibition of LonP1, including the activation of ATF4 and Nrf2, increased UPRmt markers, and a redox balance. Although CCCP and MB-10 both impaired protein import, they activated distinct downstream responses. CCCP resulted in ISR activation, while MB-10 induced Nrf2-mediated antioxidant responses. Together, these findings show that the type of mitochondrial stress determines the direction of the retrograde signaling pathways between protein homeostasis and redox signaling in muscle cells, and they provide insights on how muscle coordinates signaling pathways as part of mitochondrial adaptations to contractile activity.

Chloroplast-to-nucleus retrograde signaling and plastid RNA editing are both essential for chloroplast biogenesis and plant development, but the underlying mechanism linking these 2 processes remains unclear. Here, we identify the mitochondrial transcription termination factor mTERF3/Seedling Lethal 1 (SL1), previously characterized as a plastid-encoded RNA polymerase (PEP)-associated protein, as a key regulator connecting RNA editing to retrograde signaling. SL1 directly interacts with GUN1 and MORF2 and is indispensable for 31 out of 34 plastid RNA editing sites in Arabidopsis. Loss of SL1 function results in a strong genome uncoupled (gun) molecular phenotype under norflurazon (NF) treatment, accompanied by defective RNA editing and complete loss of the NDH complex. Mechanistically, SL1 assembles the editosome by recruiting canonical and atypical PPR-DYW proteins (CRR28, RARE1, DYW1, and DYW2) together with multiple non-PPR editing factors, while its strong affinity to MORF2 ensures appropriate editosome stoichiometry. SL1 also colocalizes with the PEP complex, suggesting a physical coupling between transcription and RNA editing in plastid nucleoids. Furthermore, SL1 modulates RNA editing profiles and regulates GLK1/2 expression during NF-induced retrograde signaling. Our findings expand the functional repertoire of mTERF proteins and uncover a molecular mechanism that connects RNA editing with retrograde signaling through SL1.

Non-Cell-Autonomous Mechanisms and Systemic Interactions in Spinal Muscular Atrophy.

Cannabidiol (CBD) has shown therapeutic potential for post-traumatic stress disorder (PTSD) by reducing spontaneous recovery (SR), yet the underlying mechanisms remain unclear. We examined the effects of CBD on SR in male and female mice and found greater behavioral efficacy in males. To uncover the molecular basis of these effects, we performed transcriptomic profiling of the prelimbic (PL) and infralimbic (IL) subregions of the medial prefrontal cortex (mPFC). We identified distinct and overlapping SR-associated gene sets in each subregion, and CBD shifted the expression of a significant subset of these genes toward non-stressed control levels, including genes involved in retrograde endocannabinoid signaling. Cross-species comparisons with human PTSD transcriptomic datasets revealed conserved gene alterations within each subregion, suggesting shared molecular signatures between mouse SR and human PTSD. These findings highlight region-specific and conserved pathways through which CBD may exert therapeutic effects and provide mechanistic insight to advance CBD-based interventions for PTSD-associated spontaneous recovery.

ERF1 modulates mitochondrial function to fine-tune ROS homeostasis and suppress ABA signaling, thereby facilitating seed germination. Seed germination represents a critical phase in the plant life cycle, and its proper regulation is crucial for optimizing crop productivity. Mitochondria are essential organelles that provide energy for seed germination in plants. However, how mitochondria fine-tune seed germination remains poorly understood. In this study, we demonstrated that ETHYLENE RESPONSE FACTOR 1 (ERF1), a key transcription factor in the canonical ethylene signaling pathway, promotes seed germination by enhancing mitochondrial function. Through the integration of gene expression, physiological and biochemical characterization, and germination analyses, we revealed that overexpression of ERF1 strengthened mitochondrial function, thereby reducing reactive oxygen species (ROS) accumulation and facilitating seed germination. Moreover, we demonstrated that overexpression of ERF1 repressed the ABA signaling pathway by inhibiting the mitochondrial retrograde signaling (MRS) pathway, thereby reducing ROS levels via downregulation of RBOHD expression and activity and enhancing sugar supply, which finally promoted seed germination. These results provide new insights into how ERF1 modulates mitochondrial function to fine-tune ROS homeostasis and suppress ABA signaling during seed germination. This work provides valuable mechanistic insights and lays the groundwork for future strategies aiming at improving seed germination in agricultural crops.

Nitrogen (N) deficiency triggers major transcriptional reprogramming in plants. The chloroplast alarmone, guanosine tetraphosphate (ppGpp) synthesized and hydrolyzed by RelA-SpoT homologs (RSHs), has been proposed to regulate cellular metabolism. Here, we characterized an Arabidopsis mutant lacking all RSHs (quadruple), which accumulates no detectable ppGpp. Transcriptome analysis showed that 774 and 2,928 nuclear-encoded genes were differentially expressed in quadruple compared with the wild type (WT), under +N and -N conditions, respectively. Upon transition from +N to -N conditions, 2,487 nuclear genes in WT and 1,505 in quadruple primarily associated with cell wall biosynthesis and defense responses, were differentially expressed, suggesting that plastidial ppGpp is involved in the reprogramming of nuclear gene expression in response to N availability. Network analysis of transcription factors (TFs) indicated that ppGpp alters TFs expression and identified 11 candidates of master regulator of TFs expression by ppGpp-dependent manner during N starvation. Transcript levels of several plastid-encoded genes were higher in quadruple compared to WT under -N conditions, whereas mitochondrial transcripts were less affected. Together, these findings suggest that ppGpp acts as both a regulator and a key component of retrograde signaling, coordinating nuclear transcription and metabolic adaptation in response to N availability.

Throughout the evolutionary history of plants, chloroplasts originating from a cyanobacterial endosymbiosis have undergone remarkable adaptation and specialization, giving rise to a multitude of plastid types. The evolution toward parasitism in plants represents a particularly extreme case of such specialization. In holoparasitic species, the relaxation of selective pressures to maintain photosynthesis has led to the progressive loss of photosynthesis-related genes and the emergence of vestigial plastids. These organelles are often highly reduced in size, frequently devoid of thylakoids and can accumulate lipids, pigments, proteins and/or starch. The study of these reduced plastids in parasitic plants is conceptually challenging yet offers a unique opportunity to uncover fundamental principles of plastid biology during evolution. In this review, we discuss recent progress in understanding the biology of these vestigial plastids, exploring their unique morphology and functions, and how photosynthesis, photoprotection and retrograde signalling have evolved. Finally, we highlight the advantages of shifting such key physiological traits for adaptation into new ecological niches for the evolutionary success of holoparasitic plants.

Prokaryotic genomes are compact and are commonly organised into operons that generate polycistronic transcripts. Plant mitochondrial genomes preserve several prokaryote-like expression features, including frequent polycistronic transcription and extensive post-transcriptional processing. At the same time, frequent rearrangement and recombination in plant mitochondria can create novel open reading frames, some of which cause cytoplasmic male sterility by perturbing mitochondrial function during pollen development. A recurring observation across species is that many sterility-associated open reading frames are co-transcribed in tandem with neighbouring mitochondrial genes, generating characteristic chimeric or extended transcripts that become key targets of nuclear fertility restorer genes. In this review, we synthesise co-transcription patterns of sterility-associated genes in two monocots (rice and maize) and two dicots (oilseed rape and sunflower), and outline how representative restorer genes recognise, cleave, destabilise, or translationally block the corresponding co-transcripts. Building on operon concepts, we discuss how co-transcription may shape transcript abundance, processing, and coupling to retrograde signalling. Finally, we summarise evidence linking sterility gene activity to reactive oxygen species homoeostasis and propose testable hypotheses for how these mitochondrial-nuclear interactions may influence plant adaptation and evolution.

Abstract In recent decades, numerous studies have shown multiple alterations of mitochondrial functions in cardiovascular diseases, metabolic conditions and neurodegeneration. The evidence for diminished oxidative phosphorylation, reduced activity of electron transport chain, increased production of reactive oxygen species, and apoptosis was interpreted as mitochondrial dysfunction. Meanwhile, it became evident that mitochondria are not just an “ATP-cow”. Mitochondria play a critical synthetic function, providing building blocks such as amino acids, nucleotides, heme, and lipids, supporting cell growth, division, signaling, and repair by releasing intermediates from mitochondria. Healthy mitochondria reduce cell inflammation and maintain redox homeostasis, modulating the production of reactive oxygen species. Mitochondrial functions are regulated by cell signaling and nuclear protein expression; however, mitochondria themselves send retrograde signals back to the nucleus, driving cell reprogramming and epigenetic modulation. This multitude of mitochondrial functions is highly flexible, supporting metabolic plasticity and cell survival under different physiological conditions. A new paradigm suggests that multiple factors promote mitochondrial functional switch. This is different from mitochondrial dysfunction due to a) reversibility of functional alterations and b) important physiological role of mitochondrial switches in the modulation of cell function. Analysis of mitochondrial functions in pathological conditions may suggest a “dysregulation” of mitochondrial functional switch, which can be normalized/rescued by targeting physiological pathways of mitochondrial regulations, such as posttranslational protein modifications (acetylation/deacetylation), lipid metabolism, and redox regulations. Meanwhile, the mitochondrial “dysfunction” paradigm became a convenient “black box” lacking mechanistic details. Defining the specific mitochondrial functions and their precise alterations can provide new therapeutic potential for targeting mitochondrial functional switches in age-related cardiovascular conditions and neurodegeneration.

Small but mighty: mitochondrial DNA at the centre of retrograde signalling.

Plant growth and stress responses are tightly linked to chloroplast retrograde signaling. Key regulators, such as the 22 kDa photosystem II protein (PsbS) and β-carbonic anhydrases (βCAs), have been implicated in photoprotection and stress acclimation. In this study, we investigated the effects of simultaneously overexpressing βCA1 and/or βCA2 in a PsbS-overexpressing Arabidopsis thaliana background. Double and triple transgenic lines (oePsbSoeβCA1, oePsbSoeβCA1βCA2) showed enhanced photoprotection, improved acclimation to fluctuating light, and greater water-use efficiency, but at the cost of reduced biomass relative to Col-0 and the npq4-1 mutant. Following bicarbonate fertilization, the triple overexpression line had improved biomass compared with oePsbS and npq4-1, but not with Col-0. Importantly, our data reveal that βCAs modulate PsbS abundance, supporting the existence of its crosstalk. Bicarbonate treatment activated stress-responsive genes and transcription factors exclusively in oePsbSoeβCAs lines, indicating heightened sensitivity associated with elevated βCAs activity. Together, these findings suggest a previously unrecognized regulatory link between βCAs activity and PsbS turnover in fine-tuning stress responses and productivity, mediated at least in part by changes in PsbS expression. However, the underlying molecular mechanisms require further investigation to determine whether these effects are specific to the PsbS level or reflect a broader role of βCAs.

The mitochondrial genes orf113b and orf146 from Xinjiang wild rapeseed cause pollen abortion in alloplasmic male sterility

TSPO-mediated mitochondrial retrograde signaling primes the microglial NLRP3 inflammasome.

Integration of whole genome resequencing and transcriptomics reveals key candidate genes and pathway for fatty acid and amino acid compositions among duck breeds.

ABSTRACTAlzheimer's disease (AD) is a progressive neurodegenerative disease that is characterized by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary Tau tangles, ultimately leading to brain atrophy and death. To elucidate the relationship between the aberrant folding and aggregation of Aβ and mutant Tau and neuronal function, we monitored neuronal activity in C. elegans AD models across age. For that, we used a neuronal GCaMP reporter to monitor fluctuations in Ca2+ and developed microfluidic devices to immobilize nematodes to non-invasively assess neuronal activity. Our findings revealed that expression of both Aβ and Tau lead to significant reductions in neuronal activity and function in young adult animals, preceding the accumulation of amyloid aggregates. Notably, Aβ expression and aggregation in muscle tissue produced detrimental effects on neuronal activity comparable to those seen after expression in neurons, suggesting that proteotoxic stress in muscle can influence neuronal function. This may occur through propagation of Aβ from muscle to neurons or through retrograde signaling pathways. Further, our new sub-stoichiometrically labeled Tau strains highlight the significant impact TauP301L,V337M has on neuronal activity throughout aging. These results enhance our understanding of the early functional effects of amyloid aggregation in Alzheimer's disease.

ABSTRACTPancreatic cancer is highly refractory and aggressive, with cancer stem cells (CSCs) being primarily responsible for its metastasis and chemoresistance. Deregulated cellular bioenergetics is a hallmark of cancer cells. However, the influence of bioenergetics on the maintenance of pancreatic CSC stemness and its underlying mechanisms have not been fully elucidated. In this study, pancreatic CSCs, isolated either by sorting ALDH+ subpopulation or enriching serially passaged tumorspheres from pancreatic cancer cells and PDX model, exhibited active mitochondrial complex I activity and increased oxidative phosphorylation. Complex I maintains stemness and tumorigenicity through its core subunit, NDUFS1. NDUFS1‐mediated pancreatic CSC stemness is reinforced by high expression of CD147, which promotes pSTAT3Tyr705‐mediated NDUFS1 transcription. To promote stemness, CD147‐NDUFS1 initiates SIRT1‐DNMT1 metaboloepigenetic signaling, decreasing promoter hypomethylation and increasing the mRNA expression of the stem cell transcript factor PAX2. Moreover, NDUFS1 and CD147 expressions were highly correlated in pancreatic cancer tissues, and their co‐expression was significantly associated with poor patient survival. Taken together, our study provides evidence that mitochondrial complex I functions as a key player in CSC stemness maintenance through NDUFS1‐mediated retrograde metaboloepigenetic signaling. Blocking a key regulator of mitonuclear communication by targeting CD147 may be a novel therapy for pancreatic cancer.

Plants adapt to environmental changes by adjusting growth and defense, and the role of epigenetic modifications in this process remains unclear. Sensing and adjusting to environmental changes are more pronounced in certain tissues such as epidermis, vasculature, meristem, and reproductive tissues. These tissues possess sensory plastids that are enriched in stress response proteins. We investigated the effects of perturbation of four sensory plastid-localized proteins, MutS HOMOLOG 1 (MSH1), PsbP DOMAIN-CONTAINING PROTEIN 3 (PPD3), CAB UNDEREXPRESSED 1 (CUE1), and 3'(2'),5'-BISPHOSPHATE NUCLEOTIDASE 1 (SAL1), on the Arabidopsis (Arabidopsis thaliana) epigenome, detecting gene expression and DNA methylation changes within gene networks associated with environmental sensing. These effects significantly overlapped with a set of CHG hypermethylated genes identified within the chromatin remodeler mutant histone deacetylase 6 (hda6) at 12-hr daylength. At 16-hr daylength, hda6 lost this CHG hypermethylation in gene bodies, and the sensory plastid mutants showed milder adjustments in phenotype and methylation- and gene expression- associated gene networks. We detected daylength-responsive epistatic interaction between sensory plastid mutants with hda6. We also found that the hda6 mutation conferred daylength memory and, with msh1, enhanced tolerance to heat and biotic stresses. These results support a model of epigenetically programmed adjustments in plant phenotype triggered by sensory plastid-to-nucleus retrograde signaling in direct response to daylength and environmental cues.