Importance of Transition Metals in Mammalian Development

The Lab

Transition metals and cell differentiation

My lab is investigating the biological roles of transition metals, such as Cu, Zn, Co, and Mn, in the development of mammalian cells. Metals play many critical roles in biology as cofactors for a variety of enzymes that are necessary for energy production, tissue maturation, signal transduction and oxidative stress resistance. Metal homeostasis requires chelation by high-affinity binding molecules, transport and sensing by transcriptional regulators to maintain low levels of free metals, as free metals participate in different toxic reactions. How organisms acquire these micronutrients and distribute them to specific cellular compartments or target proteins are subjects of intense scientific interest. Moreover, little is known about how metals and the proteins that handle and distribute them participate in processes that regulate normal growth and development. Eukaryotic genomes encode a wide variety of metal transporters and metalloproteins. Although their biochemical and metal binding properties are relatively well understood, little is known about the fine-tuned regulation of their expression, specificity for metal transport, and the redundancy of functions in the context of cell differentiation and development.

Research Focus

Copper: one ion, different cellular destinations

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My lab conducts systematic studies that combine a variety of molecular and cell biology techniques into biological models, including established cell lines and primary cultures. We incorporate diverse biochemistry techniques and combine with high resolution cutting edge synchrotron-based X-ray fluorescence spectroscopy. In particular, we study skeletal muscle differentiation as muscle present an elevated intrinsic need for transition metals like Cu for proper function. This ion is required for mitochondrial energy production as a fundamental component of cytochrome c oxidase which is elevated during the course of differentiation. We hypothesize that the proper cellular distribution of Cu+ has a leading role in the differentiation of the muscle lineage. We have evidence that support different cellular roles for Cu in addition to energy production. Moreover, we hypothesize that diverse devastating myopathies are associated with Cu deficiencies at different levels, from mitochondrial Cu-transport and function to general cellular failure in Cu homeostasis and gene regulation. We hope to provide novel molecular mechanisms that help to understand the basis of muscular phenotypes observed in mitochondrial myopathies and also in Menkes’ and Wilson’s disease patients.

Publications

Latest publications from the lab:

The mitochondrially-localized nucleoside diphosphate kinase D (NME4) is a novel metastasis suppressor. Marie-Lise Lacombe, Frederic Lamarche, Olivier De Wever, Teresita Padilla-Benavides, Alyssa Carlson, Imran Khan, Anda Huna, Sophie Vacher, Claire Calmel, Céline Desbourdes, Cécile Cottet-Rousselle, Isabelle Hininger-Favier, Stéphane Attia, Béatrice Nawrocki-Raby, Joël Raingeaud, Christelle Machon, Jérôme Guitton, Morgane Le Gall, Guilhem Clary, Cedric Broussard, Philippe Chafey, Patrice Thérond, David Bernard, Eric Fontaine, Malgorzata Tokarska-Schlattner, Patricia Steeg, Ivan Bièche, Uwe Schlattner, and Mathieu Boissan. 2021. BMC Biology. 19: 228. https://doi.org/10.1186/s12915-021-01155-5
Molecular basis of copper dysregulation and its relationship with human pathologies. May T. Maung, Alyssa Carlson, Lobna Elkhadragy, Kyle Schachtschneider, Napoleon Navarro-Tito, and Teresita Padilla-Benavides*. FASEB Journal. 35: e21810. http://dx.doi.org/10.1096/fj.202100273RR/10.3389
Impact of professional and scientific societies’ student chapters on the development of underrepresented undergraduate students. Lily Barnes, Joshua Grajales, Jocelyn Velasquez Baez, Daniel Hidalgo and Teresita Padilla-Benavides*. Frontiers in Education

Wesleyan undergraduate students



Funding

1R01AR077578-01A1 Mechanisms of Cu-binding factors to promote myogenic gene expression