Carlo Viscomi - Academia.edu (original) (raw)

Papers by Carlo Viscomi

Research paper thumbnail of Selenoprotein N1 Redox Activity Leads to Mitochondrial Dysfunction in Skeletal Muscle

Free Radical Biology and Medicine, 2017

Selenoprotein N (SEPN1), is a broadly expressed resident protein of the endoplasmic reticulum (ER... more Selenoprotein N (SEPN1), is a broadly expressed resident protein of the endoplasmic reticulum (ER) whose loss of function inexplicably leads to human muscle disease. We have defined the redox-regulated interactome of SEPN1 and identified the ER calcium import SERCA2 pump as a redox-partner of SEPN1. SEPN1 enhances SERCA2 activity by reducing luminal cysteines and cells lacking SEPN1 are conspicuously defective in ER calcium re-uptake. In addition, SEPN1 is enriched at mitochondria-associated ER membranes (MAMs), which are essential for the transfer of calcium from the ER to the mitochondria and the lack of SEPN1 results in impaired mitochondrial calcium levels and metabolic homeostasis in skeletal muscle. These observations demonstrate the involvement of SEPN1 in ER redox and calcium homeostasis and suggest that the restore of redox-dependent calcium flux, may ameliorate the myopathy of SEPN1 deficiency.

Research paper thumbnail of Mitochondrial Neurodegeneration

Cells, 2022

Mitochondria are cytoplasmic organelles, which generate energy as heat and ATP, the universal ene... more Mitochondria are cytoplasmic organelles, which generate energy as heat and ATP, the universal energy currency of the cell. This process is carried out by coupling electron stripping through oxidation of nutrient substrates with the formation of a proton-based electrochemical gradient across the inner mitochondrial membrane. Controlled dissipation of the gradient can lead to production of heat as well as ATP, via ADP phosphorylation. This process is known as oxidative phosphorylation, and is carried out by four multiheteromeric complexes (from I to IV) of the mitochondrial respiratory chain, carrying out the electron flow whose energy is stored as a proton-based electrochemical gradient. This gradient sustains a second reaction, operated by the mitochondrial ATP synthase, or complex V, which condensates ADP and Pi into ATP. Four complexes (CI, CIII, CIV, and CV) are composed of proteins encoded by genes present in two separate compartments: the nuclear genome and a small circular DNA...

Research paper thumbnail of Role of PITRM1 in Mitochondrial Dysfunction and Neurodegeneration

Mounting evidence shows a link between mitochondrial dysfunction and neurodegenerative disorders,... more Mounting evidence shows a link between mitochondrial dysfunction and neurodegenerative disorders, including Alzheimer Disease. Increased oxidative stress, defective mitodynamics, and impaired oxidative phosphorylation leading to decreased ATP production, can determine synaptic dysfunction, apoptosis, and neurodegeneration. Furthermore, mitochondrial proteostasis and the protease-mediated quality control system, carrying out degradation of potentially toxic peptides and misfolded or damaged proteins inside mitochondria, are emerging as potential pathogenetic mechanisms. The enzyme pitrilysin metallopeptidase 1 (PITRM1) is a key player in these processes; it is responsible for degrading mitochondrial targeting sequences that are cleaved off from the imported precursor proteins and for digesting a mitochondrial fraction of amyloid beta (Aβ). In this review, we present current evidence obtained from patients with PITRM1 mutations, as well as the different cellular and animal models of P...

Research paper thumbnail of Exploiting pyocyanin to treat mitochondrial disease due to respiratory complex III dysfunction

Nature Communications, 2021

Mitochondrial diseases impair oxidative phosphorylation and ATP production, while effective treat... more Mitochondrial diseases impair oxidative phosphorylation and ATP production, while effective treatment is still lacking. Defective complex III is associated with a highly variable clinical spectrum. We show that pyocyanin, a bacterial redox cycler, can replace the redox functions of complex III, acting as an electron shunt. Sub-μM pyocyanin was harmless, restored respiration and increased ATP production in fibroblasts from five patients harboring pathogenic mutations inTTC19,BCS1LorLYRM7, involved in assembly/stabilization of complex III. Pyocyanin normalized the mitochondrial membrane potential, and mildly increased ROS production and biogenesis. These in vitro effects were confirmed in bothDrosophilaTTC19KOand inDanio rerioTTC19KD, as administration of low concentrations of pyocyanin significantly ameliorated movement proficiency. Importantly, daily administration of pyocyanin for two months was not toxic in control mice. Our results point to utilization of redox cyclers for therap...

Research paper thumbnail of DNA polymerase gamma mutations that impair holoenzyme stability cause catalytic subunit depletion

Nucleic Acids Research, 2021

Mutations in POLG, encoding POLγA, the catalytic subunit of the mitochondrial DNA polymerase, cau... more Mutations in POLG, encoding POLγA, the catalytic subunit of the mitochondrial DNA polymerase, cause a spectrum of disorders characterized by mtDNA instability. However, the molecular pathogenesis of POLG-related diseases is poorly understood and efficient treatments are missing. Here, we generate the PolgA449T/A449T mouse model, which reproduces the A467T change, the most common human recessive mutation of POLG. We show that the mouse A449T mutation impairs DNA binding and mtDNA synthesis activities of POLγ, leading to a stalling phenotype. Most importantly, the A449T mutation also strongly impairs interactions with POLγB, the accessory subunit of the POLγ holoenzyme. This allows the free POLγA to become a substrate for LONP1 protease degradation, leading to dramatically reduced levels of POLγA in A449T mouse tissues. Therefore, in addition to its role as a processivity factor, POLγB acts to stabilize POLγA and to prevent LONP1-dependent degradation. Notably, we validated this mecha...

Research paper thumbnail of Correction to ‘DNA polymerase gamma mutations that impair holoenzyme stability cause catalytic subunit depletion’

Nucleic Acids Research, 2021

Research paper thumbnail of In vivo and in vitro mechanistic characterization of a clinically relevant PolγA mutation

Mutations in POLG, encoding POLγA, the catalytic subunit of the mitochondrial DNA polymerase, cau... more Mutations in POLG, encoding POLγA, the catalytic subunit of the mitochondrial DNA polymerase, cause a spectrum of disorders characterized by mtDNA instability. However, the molecular pathogenesis of POLG-related diseases is poorly understood and efficient treatments are missing. Here, we generated a POLGA449T/A449T mouse model, which reproduces the most common human recessive mutation of POLG, encoding the A467T change, and dissected the mechanisms underlying pathogenicity. We show that the A449T mutation impairs DNA binding and mtDNA synthesis activities of POLγ in vivo and in vitro. Interestingly, the A467T mutation also strongly impairs interactions with POLγB, the homodimeric accessory subunit of holo-POLγ. This allows the free POLγA to become a substrate for LONP1 protease degradation, leading to dramatically reduced levels of POLγA, which in turn exacerbates the molecular phenotypes of PolgA449T/A449T mice. Importantly, we validated this mechanism for other mutations affecting...

Research paper thumbnail of P12 A novel model of cardiomyopathy reveals a tissue specific role for the complex i assembly factor ecsit

Research paper thumbnail of A single intravenous injection of AAV-PHP.B-hNDUFS4 ameliorates the phenotype of Ndufs4 mice

Molecular Therapy - Methods & Clinical Development, 2020

Research paper thumbnail of Opa1 overexpression protects from early onset Mpv17-/--related mouse kidney disease

Moderate overexpression of Opa1, encoding a master regulator of mitochondrial cristae morphology,... more Moderate overexpression of Opa1, encoding a master regulator of mitochondrial cristae morphology, has been shown to improve significantly mitochondrial damage induced by drugs, surgical denervation, or genetically determined OXPHOS defects. However, this approach has been so far demonstrated in a limited number of genetically defective OXPHOS models characterized by specific impairment of a single mitochondrial respiratory chain complex. Here, we investigated the effectiveness of moderate Opa1 overexpression in the Mpv17-/- mouse, characterized by profound, multisystem mtDNA depletion. In naïve Mpv17-/- individuals, whose genetic background was crossed with individuals belonging to the Opa1tg strain, we found a surprising anticipation of severe, progressive focal segmental glomerulosclerosis, previously described in Mpv17-/- animals as a late-onset clinical feature (after 12-18 months of life). In contrast, kidney failure led Mpv17-/- individuals from this new “mixed” strain leading...

Research paper thumbnail of Metabolic effects of bezafibrate in mitochondrial disease

EMBO Molecular Medicine, 2020

Research paper thumbnail of Respiratory chain signalling is essential for adaptive remodelling following cardiac ischaemia

Journal of Cellular and Molecular Medicine, 2020

Research paper thumbnail of The homeostatic dynamics of feeding behaviour identify novel mechanisms of anorectic agents

Research paper thumbnail of Physical and Functional Cross-Talk Between Endo-Sarcoplasmic Reticulum and Mitochondria in Skeletal Muscle

Antioxidants & Redox Signaling, 2019

Significance: The physiological relevance of contacts between the sarcoplasmic reticulum (SR), a ... more Significance: The physiological relevance of contacts between the sarcoplasmic reticulum (SR), a specialized domain of the endoplasmic reticulum (ER) in skeletal muscle, and mitochondria is still not clear. Recent Advances: An extensive close proximity of these two organelles is a late developmental event, which suggests that it does not have an essential function. Critical Issues: The intimate association of SR/mitochondria develops during murine postnatal differentiation and the recovery of denervated atrophic muscle, which suggests that this is a highly regulated process with a specific function. Analyses of mouse models for muscle diseases suggest that impaired ER/SR-mitochondrial contacts may be due to ER stress and lead to defective bioenergetics and insulin signaling. Future Directions: Future studies are necessary to identify the molecular determinants weakening insulin signaling upon impairment of ER/mitochondrial contacts in skeletal muscles as well as to analyze the distance between SR/ER and mitochondria in muscle diseases associated with ER stress.

Research paper thumbnail of Niche stiffness underlies the ageing of central nervous system progenitor cells

Research paper thumbnail of Correction: Control of mitochondrial superoxide production by reverse electron transport at complex I

Journal of Biological Chemistry, 2019

Research paper thumbnail of Cryo-EM structures of complex I from mouse heart mitochondria in two biochemically defined states

Nature Structural & Molecular Biology, 2018

Complex I (NADH:ubiquinone oxidoreductase) uses the reducing potential of NADH to drive protons a... more Complex I (NADH:ubiquinone oxidoreductase) uses the reducing potential of NADH to drive protons across the energy-transducing inner membrane and power oxidative phosphorylation in mammalian mitochondria. Recently, cryoEM analyses have produced close-to-complete models of all 45 subunits in the bovine, ovine and porcine complexes, and identifed two states relevant to complex I in ischemia-reperfusion injury. Here, we describe the 3.3-Å structure of complex I from mouse heart mitochondria, a biomedically-relevant model system, in the 'active' state. We reveal a nucleotide bound in subunit NDUFA10, a nucleoside-kinase homolog, and define mechanistically-critical elements in the mammalian enzyme. By comparisons with a 3.9-Å structure of the 'deactive' state and with known bacterial structures we identify differences in helical geometry in the membrane domain that occur upon activation, or that alter the positions of catalytically-important charged residues. Our results demonstrate the capability of cryoEM analyses to challenge and develop mechanistic models for mammalian complex I.

Research paper thumbnail of Bioenergetic consequences of xenotopic expression of Ciona intestinalis alternative oxidase (AOX) in the mouse

Biochimica et Biophysica Acta (BBA) - Bioenergetics, 2018

Research paper thumbnail of Perturbed Redox Signaling Exacerbates a Mitochondrial Myopathy

Research paper thumbnail of Lifelong reduction in complex IV induces tissue-specific metabolic effects but does not reduce lifespan or healthspan in mice

Aging cell, Jan 25, 2018

Loss of SURF1, a Complex IV assembly protein, was reported to increase lifespan in mice despite d... more Loss of SURF1, a Complex IV assembly protein, was reported to increase lifespan in mice despite dramatically lower cytochrome oxidase (COX) activity. Consistent with this, our previous studies found advantageous changes in metabolism (reduced adiposity, increased insulin sensitivity, and mitochondrial biogenesis) in Surf1 mice. The lack of deleterious phenotypes in Surf1 mice is contrary to the hypothesis that mitochondrial dysfunction contributes to aging. We found only a modest (nonsignificant) extension of lifespan (7% median, 16% maximum) and no change in healthspan indices in Surf1 vs. Surf1 mice despite substantial decreases in COX activity (22%-87% across tissues). Dietary restriction (DR) increased median lifespan in both Surf1 and Surf1 mice (36% and 19%, respectively). We measured gene expression, metabolites, and targeted expression of key metabolic proteins in adipose tissue, liver, and brain in Surf1 and Surf1 mice. Gene expression was differentially regulated in a tiss...

Research paper thumbnail of Selenoprotein N1 Redox Activity Leads to Mitochondrial Dysfunction in Skeletal Muscle

Free Radical Biology and Medicine, 2017

Selenoprotein N (SEPN1), is a broadly expressed resident protein of the endoplasmic reticulum (ER... more Selenoprotein N (SEPN1), is a broadly expressed resident protein of the endoplasmic reticulum (ER) whose loss of function inexplicably leads to human muscle disease. We have defined the redox-regulated interactome of SEPN1 and identified the ER calcium import SERCA2 pump as a redox-partner of SEPN1. SEPN1 enhances SERCA2 activity by reducing luminal cysteines and cells lacking SEPN1 are conspicuously defective in ER calcium re-uptake. In addition, SEPN1 is enriched at mitochondria-associated ER membranes (MAMs), which are essential for the transfer of calcium from the ER to the mitochondria and the lack of SEPN1 results in impaired mitochondrial calcium levels and metabolic homeostasis in skeletal muscle. These observations demonstrate the involvement of SEPN1 in ER redox and calcium homeostasis and suggest that the restore of redox-dependent calcium flux, may ameliorate the myopathy of SEPN1 deficiency.

Research paper thumbnail of Mitochondrial Neurodegeneration

Cells, 2022

Mitochondria are cytoplasmic organelles, which generate energy as heat and ATP, the universal ene... more Mitochondria are cytoplasmic organelles, which generate energy as heat and ATP, the universal energy currency of the cell. This process is carried out by coupling electron stripping through oxidation of nutrient substrates with the formation of a proton-based electrochemical gradient across the inner mitochondrial membrane. Controlled dissipation of the gradient can lead to production of heat as well as ATP, via ADP phosphorylation. This process is known as oxidative phosphorylation, and is carried out by four multiheteromeric complexes (from I to IV) of the mitochondrial respiratory chain, carrying out the electron flow whose energy is stored as a proton-based electrochemical gradient. This gradient sustains a second reaction, operated by the mitochondrial ATP synthase, or complex V, which condensates ADP and Pi into ATP. Four complexes (CI, CIII, CIV, and CV) are composed of proteins encoded by genes present in two separate compartments: the nuclear genome and a small circular DNA...

Research paper thumbnail of Role of PITRM1 in Mitochondrial Dysfunction and Neurodegeneration

Mounting evidence shows a link between mitochondrial dysfunction and neurodegenerative disorders,... more Mounting evidence shows a link between mitochondrial dysfunction and neurodegenerative disorders, including Alzheimer Disease. Increased oxidative stress, defective mitodynamics, and impaired oxidative phosphorylation leading to decreased ATP production, can determine synaptic dysfunction, apoptosis, and neurodegeneration. Furthermore, mitochondrial proteostasis and the protease-mediated quality control system, carrying out degradation of potentially toxic peptides and misfolded or damaged proteins inside mitochondria, are emerging as potential pathogenetic mechanisms. The enzyme pitrilysin metallopeptidase 1 (PITRM1) is a key player in these processes; it is responsible for degrading mitochondrial targeting sequences that are cleaved off from the imported precursor proteins and for digesting a mitochondrial fraction of amyloid beta (Aβ). In this review, we present current evidence obtained from patients with PITRM1 mutations, as well as the different cellular and animal models of P...

Research paper thumbnail of Exploiting pyocyanin to treat mitochondrial disease due to respiratory complex III dysfunction

Nature Communications, 2021

Mitochondrial diseases impair oxidative phosphorylation and ATP production, while effective treat... more Mitochondrial diseases impair oxidative phosphorylation and ATP production, while effective treatment is still lacking. Defective complex III is associated with a highly variable clinical spectrum. We show that pyocyanin, a bacterial redox cycler, can replace the redox functions of complex III, acting as an electron shunt. Sub-μM pyocyanin was harmless, restored respiration and increased ATP production in fibroblasts from five patients harboring pathogenic mutations inTTC19,BCS1LorLYRM7, involved in assembly/stabilization of complex III. Pyocyanin normalized the mitochondrial membrane potential, and mildly increased ROS production and biogenesis. These in vitro effects were confirmed in bothDrosophilaTTC19KOand inDanio rerioTTC19KD, as administration of low concentrations of pyocyanin significantly ameliorated movement proficiency. Importantly, daily administration of pyocyanin for two months was not toxic in control mice. Our results point to utilization of redox cyclers for therap...

Research paper thumbnail of DNA polymerase gamma mutations that impair holoenzyme stability cause catalytic subunit depletion

Nucleic Acids Research, 2021

Mutations in POLG, encoding POLγA, the catalytic subunit of the mitochondrial DNA polymerase, cau... more Mutations in POLG, encoding POLγA, the catalytic subunit of the mitochondrial DNA polymerase, cause a spectrum of disorders characterized by mtDNA instability. However, the molecular pathogenesis of POLG-related diseases is poorly understood and efficient treatments are missing. Here, we generate the PolgA449T/A449T mouse model, which reproduces the A467T change, the most common human recessive mutation of POLG. We show that the mouse A449T mutation impairs DNA binding and mtDNA synthesis activities of POLγ, leading to a stalling phenotype. Most importantly, the A449T mutation also strongly impairs interactions with POLγB, the accessory subunit of the POLγ holoenzyme. This allows the free POLγA to become a substrate for LONP1 protease degradation, leading to dramatically reduced levels of POLγA in A449T mouse tissues. Therefore, in addition to its role as a processivity factor, POLγB acts to stabilize POLγA and to prevent LONP1-dependent degradation. Notably, we validated this mecha...

Research paper thumbnail of Correction to ‘DNA polymerase gamma mutations that impair holoenzyme stability cause catalytic subunit depletion’

Nucleic Acids Research, 2021

Research paper thumbnail of In vivo and in vitro mechanistic characterization of a clinically relevant PolγA mutation

Mutations in POLG, encoding POLγA, the catalytic subunit of the mitochondrial DNA polymerase, cau... more Mutations in POLG, encoding POLγA, the catalytic subunit of the mitochondrial DNA polymerase, cause a spectrum of disorders characterized by mtDNA instability. However, the molecular pathogenesis of POLG-related diseases is poorly understood and efficient treatments are missing. Here, we generated a POLGA449T/A449T mouse model, which reproduces the most common human recessive mutation of POLG, encoding the A467T change, and dissected the mechanisms underlying pathogenicity. We show that the A449T mutation impairs DNA binding and mtDNA synthesis activities of POLγ in vivo and in vitro. Interestingly, the A467T mutation also strongly impairs interactions with POLγB, the homodimeric accessory subunit of holo-POLγ. This allows the free POLγA to become a substrate for LONP1 protease degradation, leading to dramatically reduced levels of POLγA, which in turn exacerbates the molecular phenotypes of PolgA449T/A449T mice. Importantly, we validated this mechanism for other mutations affecting...

Research paper thumbnail of P12 A novel model of cardiomyopathy reveals a tissue specific role for the complex i assembly factor ecsit

Research paper thumbnail of A single intravenous injection of AAV-PHP.B-hNDUFS4 ameliorates the phenotype of Ndufs4 mice

Molecular Therapy - Methods & Clinical Development, 2020

Research paper thumbnail of Opa1 overexpression protects from early onset Mpv17-/--related mouse kidney disease

Moderate overexpression of Opa1, encoding a master regulator of mitochondrial cristae morphology,... more Moderate overexpression of Opa1, encoding a master regulator of mitochondrial cristae morphology, has been shown to improve significantly mitochondrial damage induced by drugs, surgical denervation, or genetically determined OXPHOS defects. However, this approach has been so far demonstrated in a limited number of genetically defective OXPHOS models characterized by specific impairment of a single mitochondrial respiratory chain complex. Here, we investigated the effectiveness of moderate Opa1 overexpression in the Mpv17-/- mouse, characterized by profound, multisystem mtDNA depletion. In naïve Mpv17-/- individuals, whose genetic background was crossed with individuals belonging to the Opa1tg strain, we found a surprising anticipation of severe, progressive focal segmental glomerulosclerosis, previously described in Mpv17-/- animals as a late-onset clinical feature (after 12-18 months of life). In contrast, kidney failure led Mpv17-/- individuals from this new “mixed” strain leading...

Research paper thumbnail of Metabolic effects of bezafibrate in mitochondrial disease

EMBO Molecular Medicine, 2020

Research paper thumbnail of Respiratory chain signalling is essential for adaptive remodelling following cardiac ischaemia

Journal of Cellular and Molecular Medicine, 2020

Research paper thumbnail of The homeostatic dynamics of feeding behaviour identify novel mechanisms of anorectic agents

Research paper thumbnail of Physical and Functional Cross-Talk Between Endo-Sarcoplasmic Reticulum and Mitochondria in Skeletal Muscle

Antioxidants & Redox Signaling, 2019

Significance: The physiological relevance of contacts between the sarcoplasmic reticulum (SR), a ... more Significance: The physiological relevance of contacts between the sarcoplasmic reticulum (SR), a specialized domain of the endoplasmic reticulum (ER) in skeletal muscle, and mitochondria is still not clear. Recent Advances: An extensive close proximity of these two organelles is a late developmental event, which suggests that it does not have an essential function. Critical Issues: The intimate association of SR/mitochondria develops during murine postnatal differentiation and the recovery of denervated atrophic muscle, which suggests that this is a highly regulated process with a specific function. Analyses of mouse models for muscle diseases suggest that impaired ER/SR-mitochondrial contacts may be due to ER stress and lead to defective bioenergetics and insulin signaling. Future Directions: Future studies are necessary to identify the molecular determinants weakening insulin signaling upon impairment of ER/mitochondrial contacts in skeletal muscles as well as to analyze the distance between SR/ER and mitochondria in muscle diseases associated with ER stress.

Research paper thumbnail of Niche stiffness underlies the ageing of central nervous system progenitor cells

Research paper thumbnail of Correction: Control of mitochondrial superoxide production by reverse electron transport at complex I

Journal of Biological Chemistry, 2019

Research paper thumbnail of Cryo-EM structures of complex I from mouse heart mitochondria in two biochemically defined states

Nature Structural & Molecular Biology, 2018

Complex I (NADH:ubiquinone oxidoreductase) uses the reducing potential of NADH to drive protons a... more Complex I (NADH:ubiquinone oxidoreductase) uses the reducing potential of NADH to drive protons across the energy-transducing inner membrane and power oxidative phosphorylation in mammalian mitochondria. Recently, cryoEM analyses have produced close-to-complete models of all 45 subunits in the bovine, ovine and porcine complexes, and identifed two states relevant to complex I in ischemia-reperfusion injury. Here, we describe the 3.3-Å structure of complex I from mouse heart mitochondria, a biomedically-relevant model system, in the 'active' state. We reveal a nucleotide bound in subunit NDUFA10, a nucleoside-kinase homolog, and define mechanistically-critical elements in the mammalian enzyme. By comparisons with a 3.9-Å structure of the 'deactive' state and with known bacterial structures we identify differences in helical geometry in the membrane domain that occur upon activation, or that alter the positions of catalytically-important charged residues. Our results demonstrate the capability of cryoEM analyses to challenge and develop mechanistic models for mammalian complex I.

Research paper thumbnail of Bioenergetic consequences of xenotopic expression of Ciona intestinalis alternative oxidase (AOX) in the mouse

Biochimica et Biophysica Acta (BBA) - Bioenergetics, 2018

Research paper thumbnail of Perturbed Redox Signaling Exacerbates a Mitochondrial Myopathy

Research paper thumbnail of Lifelong reduction in complex IV induces tissue-specific metabolic effects but does not reduce lifespan or healthspan in mice

Aging cell, Jan 25, 2018

Loss of SURF1, a Complex IV assembly protein, was reported to increase lifespan in mice despite d... more Loss of SURF1, a Complex IV assembly protein, was reported to increase lifespan in mice despite dramatically lower cytochrome oxidase (COX) activity. Consistent with this, our previous studies found advantageous changes in metabolism (reduced adiposity, increased insulin sensitivity, and mitochondrial biogenesis) in Surf1 mice. The lack of deleterious phenotypes in Surf1 mice is contrary to the hypothesis that mitochondrial dysfunction contributes to aging. We found only a modest (nonsignificant) extension of lifespan (7% median, 16% maximum) and no change in healthspan indices in Surf1 vs. Surf1 mice despite substantial decreases in COX activity (22%-87% across tissues). Dietary restriction (DR) increased median lifespan in both Surf1 and Surf1 mice (36% and 19%, respectively). We measured gene expression, metabolites, and targeted expression of key metabolic proteins in adipose tissue, liver, and brain in Surf1 and Surf1 mice. Gene expression was differentially regulated in a tiss...