Regulation of mitochondrial oxidative phosphorylation
The Manfredi Lab has contributed to many seminal findings on the genetic and the biochemical characteristics of disorders involving the regulation of mitochondrial oxidative phosphorylation. In addition to generating novel cybrid cell lines, which contain human mutant mtDNA transferred into mtDNA-less cells, we have developed novel approaches to deliver recombinant proteins to mitochondria to correct mtDNA mutations
The Manfredi Lab discovered a novel pathway involving soluble adenylyl cyclase (sAC) localized in mitochondria that senses metabolic demands and activates, through cAMP, protein kinases, which then regulate the activities of mitochondrial enzymes. This metabolic regulatory pathway is currently under ongoing investigation in our lab.
- Rescue of a deficiency in ATP synthesis by transfer of MTATP6, a mitochondrial DNA-encoded gene, to the nucleus. (Nat Genet, 2002)
- Respiratory chain supercomplexes set the threshold for respiration defects in human mtDNA mutant cybrids. (Hum Mol Genet, 2006)
- The mitochondrial respiratory chain is a modulator of apoptosis. (J Cell Biol, 2006)
- Cyclic AMP produced inside mitochondria regulates oxidative phosphorylation. (Cell Metab, 2009)
- Modulation of mitochondrial protein phosphorylation by soluble adenylyl cyclase ameliorates cytochrome oxidase defects. (EMBO Mol Med, 2009)
- Protein phosphorylation and prevention of cytochrome oxidase inhibition by ATP: coupled mechanisms of energy metabolism regulation. (Cell Metab, 2011)
- cAMP and mitochondria. (Physiology, 2013)
- Rewiring of Glutamine Metabolism Is a Bioenergetic Adaptation of Human Cells with Mitochondrial DNA Mutations. (Cell Metab, 2018)
Amyotrophic lateral sclerosis
The Manfredi Lab pioneered research on the involvement of mitochondria in amyotrophic lateral sclerosis (ALS). We demonstrated that mitochondria are dysfunctional in the CNS of mouse models of familial ALS, resulting in defects of energy production. We showed that mutant SOD1, which is one of the most common causes of familial ALS, is accumulated and misfolded in mitochondria. We also pioneered the study of calcium dysregulation in mitochondria of mutant SOD1 mice. We then demonstrated the molecular mechanisms whereby SOD1 import in the mitochondrial intermembrane space is regulated under normal conditions, and we demonstrated how these mechanisms fail in mutant SOD1 cells, resulting in pathological protein aggregation. In addition, we are carrying out a mechanistic investigation of familial ALS/FTD associated with mutations of the mitochondrial protein CHCHD10.
- Mutant superoxide dismutase 1 forms aggregates in the brain mitochondrial matrix of amyotrophic lateral sclerosis mice. (J Neurosci, 2005)
- Different regulation of wild-type and mutant Cu,Zn superoxide dismutase localization in mammalian mitochondria. (Hum Mol Genet, 2008)
- The mitochondrial calcium regulator cyclophilin D is an essential component of estrogen-mediated neuroprotection in amyotrophic lateral sclerosis. (Brain, 2012)
- In vitro and in vivo studies of the ALS-FTLD protein CHCHD10 reveal novel mitochondrial topology and protein interactions. (Hum Mol Genet, 2018)
- LS/FTD mutant CHCHD10 mice reveal a tissue-specific toxic gain-of-function and mitochondrial stress response. (Acta Neuropathol, 2019)
- Nrf2 signaling links ER oxidative protein folding and calcium homeostasis in health and disease. (Life Science Alliance, 2019)
Imaging of mitochondrial transport and quality control in ALS
The Manfredi Lab developed new imaging tools to investigate mitochondrial axonal transport in motor neurons. These tools were used to demonstrate that the dynamics of mitochondria is impaired in SOD1 mutant motor neurons in culture and in vivo in adult mice. By generating new transgenic mice, in which SOD1 is selectively targeted to the mitochondrial intermembrane space (IMS), we have demonstrated that the mutant protein localized in mitochondria plays a direct role in causing neurodegeneration in vivo. In this context, the protein accumulation and misfolding triggers a special form of mitochondrial unfolded protein response that plays an adaptive role and could be protective in neurons affected by mutant SOD1.
- Mutant SOD1 in neuronal mitochondria causes toxicity and mitochondrial dynamics abnormalities. (Hum Mol Genet, 2009)
- In vivo pathogenic role of mutant SOD1 localized in the mitochondrial intermembrane space (J Neurosci, 2011)
- Mitochondrial dynamics and bioenergetic dysfunction is associated with synaptic alterations in mutant SOD1 motor neurons (J Neurosci, 2012)
- Sex specific activation of the ERα axis of the mitochondrial UPR (UPRmt) in the G93A-SOD1 mouse model of familial ALS. (Hum Mol Genet, 2017)
- Parkin is a disease modifier in the mutant SOD1 mouse model of ALS.(Embo Mol Med, 2018)
- Raloxifene is a Female-specific Proteostasis Therapeutic in the Spinal Cord. (Endocrinology, 2020)
- Proteasome mapping reveals sexual dimorphism in tissue-specific sensitivity to protein aggregations. (EMBO Rep, 2020)
Metabolic profiling of ALS
Our recent contributions to the field of metabolic involvement in ALS include work on the metabolic profiling of sporadic and familial ALS cases, with the goal of identifying novel tools for stratifying ALS patients and developing personalized therapies.
- Bioenergetic markers in skin fibroblasts of sporadic amyotrophic lateral sclerosis and progressive lateral sclerosis patients. (Ann Neurol, 2014)
- Fibroblast bioenergetics to classify amyotrophic lateral sclerosis patients. (Mol Neurodegener, 2017)
- Accelerated transsulfuration metabolically defines a discrete subclass of amyotrophic lateral sclerosis patients. (Neurobiol Dis, 2020)