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.

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.

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.

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.

All Manfredi Lab Publications

Weill Cornell Medicine Manfredi Lab 407 East 61st Street, 5th Floor New York, NY 10065 Phone: (646) 962-8271