To adapt to changing environments cells must signal. Recent advances in mitochondrial studies show that mitochondria play a key role in cell sensing and cell signaling. These organelles undergo dynamic and complex remodeling of shape, motility, metabolism, and proteome in response to environmental stimuli and energetic requirements during growth and development. The failure of mitochondria to integrate into signal transduction cascades is indeed the most common cause of inborn errors of metabolism. It is also linked to virtually all age-associated diseases and to autoimmunity, heart disease, diabetes, and cancer.

Although, we have made tremendous progress in identifying the mitochondrial proteins of several tissues and organisms, we know very little about how these individual parts are coordinated in response to both physiological and pathological stimuli.

• What are the molecular links between cellular signals and mitochondrial responses?

• What are the mitochondrial proteins that sense, modulate, and propagate cellular signaling cascades?

• How is the mitochondrial signaling “toolkit” regulated?

• What happens when mitochondrial signaling pathways are compromised and how might these be targeted therapeutically?

Our goal is to characterize mitochondrial signal transduction cascades that occur in response to physiological and pathophysiological stimuli. We develop experimental and computational strategies to predict, test, and reverse the effects of genetic and chemical perturbations on several mitochondrial functions. Our approach is Systematic, because it employs large-scale, unbiased survey of mitochondrial physiology, and it is Integrative, because it combines heterogeneous yet complementary data-sets.

Jennifer Wettmarshausen

Anja Leimpek

Utkarsh Tripathi

Dr. Yiming Cheng

Dr. Matteo Gorza

Simge Yuz

Dr. Nisha Verma

Rorbach J, Boesch P, Gammage PA, Nicholls TJ, Pearce SF, Patel D, Hauser A, Perocchi F, Minczuk M (2014). MRM2 and MRM3 are involved in biogenesis of the large subunit of the mitochondrial ribosome. Mol Biol Cell 25(17):2542-55.

Baughman JM*, Perocchi F*, Girgis HS, Plovanich M, Belcher-Timme CA, Sancak Y, Bao XR, Strittmatter L, Goldberger O, Bogorad RL, Koteliansky V, Mootha VK (2011). Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature. 476(7360):341-5.

Perocchi F, Gohil VM, Girgis HS, Bao XR, McCombs JE, Palmer AE, Mootha VK (2010). MICU1 encodes a mitochondrial EF hand protein required for Ca(2+) uptake. Nature. 467(7313):291-6.

Gohil VM*, Sheth SA*, Nilsson R, Wojtovich AP, Lee JH, Perocchi F, Chen W, Clish CB, Ayata C, Brookes PS, Mootha VK (2010). Nutrient-sensitized screening for drugs that shift energy metabolism from mitochondrial respiration to glycolysis. Nature Biotechnology. 28(3):249-55.

Gagneur J, Sinha H, Perocchi F, Bourgon R, Huber W, Steinmetz LM (2009). Genome-wide allele- and strand-specific expression profiling. Molecular Systems Biology. 5:274.

Xu Z*, Wei W*, Gagneur J, Perocchi F, Clauder-Münster S, Camblong J, Guffanti E, Stutz F, Huber W, Steinmetz LM (2009). Bidirectional promoters generate pervasive transcription in yeast. Nature. 457(7232):1033-7.

Perocchi F*, Mancera E*, Steinmetz LM (2008). Systematic screens for human disease genes, from yeast to human and back. Molecular Biosystems. 4(1):18-29.

Perocchi F*, Xu Z*, Clauder-Münster S, Steinmetz LM (2007). Antisense artifacts in transcriptome microarray experiments are resolved by actinomycin D. Nucleic Acids Research. 35(19):e128.

Perocchi F, Jensen LJ, Gagneur J, Ahting U, von Mering C, Bork P, Prokisch H, Steinmetz LM (2006). Assessing systems properties of yeast mitochondria through an interaction map of the organelle. PLoS Genetics. 2(10):e170.

PRESS AND MEDIA

Mystery of the mitochondria

June 22, 2011

The Broad Institute | Blog

Cell's linchpin protein found: Discovery ends 50-year search for calcium channel

June 19, 2011

Harvard University | The Harvard Gazette

Mitochondrial mystery demystified

June 17, 2011

The Broad Institute | News and Publications

Celebrating prize-winning MGH research

April 22, 2011

Massachusetts General Hospital | MGH News

Cracking Open a Cell Biology Mystery

August 8, 2010

The Broad Institute | Research News