Tale

The Shapes of Energy

Luke Chao

Massachusetts General Hospital

Published December 12, 2024

In Woods Hole, Mass., the Atlantic breeze mixes with the hum of microscopes and the chatter of biologists. There, in a summer neurobiology course, Luke Chao first became enthralled by mitochondria “whizzing” around the neurons in a mouse.

“It was just really cool,” he recalls, describing the tiny organelles as they traveled along the long projections of nerve cells (axons), in a model of neurological damage.

This inspirational moment has since grown into the focus of the Chao Lab at Massachusetts General Hospital (MGH) in Boston. There, the Chao team explores the dynamic and enigmatic architecture of cellular membranes, particularly those of mitochondria, which provide energy for the cells in our bodies.

Two membrane layers form mitochondria, but the hub of energy production is the wrinkled inner layer folds, called cristae, which are distinctive for their intricate and diverse shapes.

The wrinkled folds of mitochondrial crista (courtesy L. Chao) resemble the zigzag coastline of Maine. (credit: NOAA).

“The folds can come in tubular forms,” Chao says. “Or they can come in sheets. One can describe them like pasta geometries — lasagna (lamellar, or sheet-like), or penne (tubular). It has remained a mystery how the different forms are made, and how the different shapes facilitate the organelle’s varied functions.”

Chao has had an interest in the classic structural questions about the atomic arrangement of individual proteins that sculpt mitochondria. But he’s also interested in the bigger picture — how multiple proteins come together in unique and special combinations to build membrane architectures in cells.

“We'd like to understand on a very fundamental level how cristae are made,” he says, “to understand structure-function relationships of how proteins influence membranes.” Understanding how shapes change under different conditions could shed light on diseases such as neurodegeneration, cancer and aging, where mitochondrial dysfunction is an early and important player.

Chao grew up in Chelmsford, Mass. During his undergraduate years at Brandeis University, he took a work-study job washing dishes in a biochemistry lab. “I just loved the environment,” he says. “Everyone working together, fumbling in the dark trying to figure things out.”

Chao went on to pursue a Ph.D. at the University of California, Berkeley, under the mentorship of structural biologist John Kuriyan. There, Chao developed a fascination with the “amazing acrobatics” of proteins, uncovering their roles as dynamic machines that reconfigure themselves to perform vital cellular functions.

His doctoral work focused on the calcium/calmodulin-dependent protein kinase II (CaMKII) holoenzyme, a large oligomeric molecule central to neuron and cardiac calcium signaling. His findings revealed mechanisms of protein activation and inhibition, illuminating how these molecular giants operate with precision in living cells.

Postdoctoral work in the laboratory of Stephen Harrison at Harvard Medical School introduced Chao to the realm of membranes and viruses, specifically flaviviruses, a family that includes Dengue, West Nile and Zika. There, he investigated the conformational changes that proteins undergo to mediate membrane fusion—a process crucial in viral entry.

Toward the end of his postdoc, Chao pondered his next move. He recalled his experience with mitochondria at the Marine Biology Laboratory in Woods Hole and saw new opportunities to explore protein acrobatics and membrane biology.

“To me, it’s a fascinating medium for investigating shape and motion across scales,” he says. “Obviously, there are the individual lipids, their position, their composition—all of these details matter to generate the right environment for the proteins to work. But the proteins themselves also act on the fluid bilayer to generate highly specialized local environments. There are fantastic opportunities for integrative understanding of these relationships at multiple levels. We still do not understand how all of these factors work together to generate a living, breathing organelle.”

In 2016, Chao launched his independent lab at MGH, diving into the dynamic architecture of mitochondria. On one level, the Chao group studies mitochondrial fusion with in vitro techniques, similar to the viral fusion experiments of his postdoctoral training, reconstituting essential components to answer detailed mechanistic questions (Ge et al., eLife 2020). By isolating proteins and recreating the membrane environments in the lab, Chao can dissect membrane fusion and protein-membrane intermediates.

On another level, his work leverages techniques such as cryo-electron tomography (cryo-ET), which allows researchers to freeze cells and capture 3D snapshots of their inner workings. It’s a way to see structures “in their native context,” he notes, avoiding the artifacts introduced by methods that rely on fixation and staining.

An area of focus for Chao’s lab is the protein Opa1, which reshapes mitochondrial cristae in response to stress. In a recent study, Chao and his team examined how Opa1’s state alters cristae structures. The findings revealed that mitochondrial membranes can adapt dynamically, reshaping themselves to meet the energy demands of the cell or to respond to environmental challenges (Fry, Navarro, et. al, EMBO J, 2024).

Chao also looks at these questions through an evolutionary lens. The origin of mitochondria has been dated to over a billion years ago—a time when primordial archaea absorbed an alphaproteobacteria, the mitochondrial precursor.

“There are bacterial analogues of cristae, called intra-cytoplasic membranes,” he says. “The common theme is that they help provide additional real estate to pack in different biosynthetic enzymes, similar to how the expanded surface area of the mitochondrial inner-membrane packs in a lot of respiratory chain proteins. So there might be some conserved principles in how they are built, and some interesting differences too.”

In collaborations, he partners with MGH colleagues, labs in the Boston area, as well as groups internationally. Locally, his home Department of Molecular Biology at MGH has “people doing all sorts of interesting things, from prokaryotic immunity and cilia dynamics, to RNAs, plant and chromatin biology,” feeding his intellectual curiosity.

SBGrid member Luke Chao in his office (Courtesy L. Chao).

Outside the lab, Chao and his family often escape to explore the mountains of New England and enjoy Maine’s rugged coastline, a place reminiscent of mitochondria cristae. “There are so many inlets that if you take the tidal coastline of Maine, its actually greater than that of California. It’s all about surface area. There is a lot to explore.”

--Carol Cruzan Morton

Other tales

Mind and Muscle

Ryan Hibbs

Published 28 March 2025

The Shapes of Energy

Luke Chao

Published 12 December 2024

Predicting Proteins

Jens Meiler

Published 25 November 2024

Death Metal

Steven Damo

Published 28 April 2024

Context Matters

Bing Chen

Published 30 January 2024

The Crystal Whisperer

Sarah Bowman

Published 29 November 2023

Data in Motion

Nozomi Ando

Published 29 September 2023

The Monstrous Maw

André Hoelz

Published 28 June 2023

Second Takes

Andrea Thorn

Published 28 February 2023

Radical reactions

Yvain Nicolet

Published 31 January 2023

Floppy Physics

Eva Nogales

Published 30 November 2022

Structure of Equity

Jamaine Davis

Published 28 September 2022

Life and Death of a Cell

Evris Gavathiotis

Published 28 July 2022

Follow the glow

Kurt Krause

Published 29 April 2022

Resolution solutions

Willy Wriggers

Published 25 February 2022

Of enzymes and membranes

Ming Zhou

Published 28 October 2021

Step-by-step

Gabrielle Rudenko

Published 26 September 2021

Moving muscle

Montserrat Samso

Published 26 July 2021

Particle catcher

Stefan Raunser

Published 28 June 2021

Designer drugs

Ho Leung Ng

Published 25 February 2021

Right place, right time

Ernesto Fuentes

Published 29 January 2021

Shape-shifting secrets of membranes

James Hurley

Published 27 November 2020

Enzymatic action

Cynthia Wolberger

Published 28 September 2020

Rules of motion

Priyamvada Acharya

Published 31 July 2020

Cosmic Squared

Michael Cianfrocco

Published 27 June 2020

Kaps are Cool

Yuh Min Chook

Published 28 April 2020

Spiraling into focus

Carsten Sachse

Published 29 March 2020

Seeing cilia

Alan Brown

Published 27 February 2020

For the Love of EM

Guy Schoehn

Published 27 January 2020

Protein Puddles

Michael Rosen

Published 16 December 2019

Changing channels

Daniel Minor Jr.

Published 27 September 2019

Listening Tips

Marcos Sotomayor

Published 30 July 2019

Beyond Cool

Published 31 May 2019

Hao Wu

A Higher Order

Published 30 May 2019

Aye Aye Captain

Alexandre Bonvin

Published 29 April 2019

The PARP Family Family

John Pascal

Published 28 February 2019

Frame by frame

Nikolaus Grigorieff

Published 28 January 2019

Predicting Success

Bil Clemons

Published 18 December 2018

Curiouser and Curiouser

Ramaswamy Subramanian

Published 27 November 2018

Rely on This

Sjors Scheres

Published 26 October 2018

Proteins out of bounds

Gerhard Wagner

Published 27 September 2018

Hiding in plain sight

Gaya Amarasinghe

Published 27 July 2018

Jumping Genes

Orsolya Barabas

Published 27 June 2018

Data Whisperer

Karolin Luger

Published 30 May 2018

Flipping the Switch

Jacqueline Cherfils

Published 27 April 2018

Tooling Around

Andrew Kruse

Published 29 March 2018

Comings and Goings

Tom Rapoport, Ph.D.

Published 23 February 2018

Transcriptional Rhythm

Seth Darst

Published 27 January 2018

The Language of Gene Regulation

Daniel Panne

Published 21 November 2017

Not Your Average Protein

James Fraser

Published 23 October 2017

Message Received

Sebastien Granier

Published 24 August 2017

Resistance is Futile

Celia Schiffer

Published 28 July 2017

Twist of Fate

Leemor Joshua-Tor

Published 28 June 2017

Drug Designer

John Buolamwini

Published 30 May 2017

Mathematically Minded

James Holton

Published 28 April 2017

Garbage Out

Kay Diederichs

Published 30 March 2017

Fixer Upper

Brandt Eichman

Published 27 February 2017

Mobilizers

Phoebe Rice

Published 31 January 2017

Escape Artist

Katya Heldwein

Published 19 December 2016

Nature’s Confectioner

Jochen Zimmer

Published 29 November 2016

State of Fusion

Jason McLellan

Published 27 October 2016

Here Be Dragons

Brian Fox

Published 28 September 2016

SBGrid Assumes Ownership of PyMOLWiki

Published 15 September 2016

Pharm Team

Oleg Tsodikov

Published 24 August 2016

Spiro-Gyra

Alejandro Buschiazzo

Published 27 July 2016

Turning the DIALS

Nicholas Sauter

Published 29 June 2016

Pipeline Dreams

Bridget Carragher and Clint Potter

Published 26 April 2016

U-Store-It

The SBGrid Data Bank provides an affordable and sustainable way to preserve and share structural biology data

Published 28 March 2016

Big Questions, Big Answers

Jennifer Doudna

Published 22 February 2016

Not a Structural Biologist

Enrico Di Cera

Published 17 December 2015

Divide and Conquer

Kevin Corbett

Published 19 November 2015

Computing Cellular Clockworks

Klaus Schulten

Published 23 October 2015

Trans-Plant

Gang Dong

Published 26 September 2015

Keep on Moving

James Berger

Published 23 August 2015

Totally Tubular

Antonina Roll-Mecak

Published 27 July 2015

From Disorder, Function

Julie Forman-Kay

Published 29 June 2015

Into Alignment

Geoff Barton

Published 27 May 2015

Two Labs, Many Methods

Michael Sattler

Published 28 April 2015

Picture This

Georgios Skiniotis

Published 20 March 2015

Intron Intrigue

Navtej Toor

Published 20 February 2015

Cut and Paste

Martin Jinek

Published 28 January 2015

Basics and Beyond

Qing Fan

Published 18 December 2014

Bloodletting and Other Studies

Pedro José Barbosa Pereira

Published 25 November 2014

Wire Models, Wired

A brief history of UCSF Chimera

Published 29 October 2014

In Search of…New Drugs

Doug Daniels

Published 30 September 2014

An Affinity for Affinity…and Corals

John C. Williams

Published 29 August 2014

Pete Meyer, Ph.D.

Research Computing Specialist

Published 22 August 2014

Justin O'Connor

Sr. System Administrator

Published 20 August 2014

Carol Herre

Software Release Engineer

Published 15 August 2014

Elizabeth Dougherty

Science Writer

Published 13 August 2014

Andrew Morin, Ph.D.

Policy Research Fellow

Published 11 August 2014

Jason Key, Ph.D.

Associate Director of Technology and Innovation

Published 8 August 2014

Piotr Sliz, Ph.D.

Principal Investigator, SBGrid

Published 1 August 2014

New Kid on the Block

James Chen

Published 29 July 2014

Membrane Master

Tamir Gonen

Published 30 June 2014

The Natural Bridge

Piotr Sliz

Published 13 June 2014

Surprise, Surprise

Catherine Drennan

Published 26 April 2014

Gone Viral

Olve Peersen

Published 20 March 2014

All Who Wander Are Not Lost

Frank Delaglio

Published 24 February 2014

The Raw and the Cooked

Graeme Winter

Published 24 January 2014

Vacc-elerator

Peter Kwong

Published 17 December 2013

Structural Storyteller

Karin Reinisch

Published 15 November 2013

The Fixer

Jane Richardson

Published 28 October 2013

Inside the Box

Mishtu Dey

Published 17 September 2013

Sensing a Change

Brian Crane

Published 16 August 2013

Towards Personalized Oncology

Mark Lemmon

Published 16 July 2013

Brush with Fame

Yizhi Jane Tao

Published 14 June 2013

Toxic Avenger

Borden Lacy

Published 21 May 2013

Pushing the Boundaries

Stephen Harrison

Published 22 April 2013

Strength in Numbers

Joseph Ho

Published 18 March 2013

One Lab, Many Methods

Wesley Sundquist

Published 12 February 2013

Unplanned Pioneer

Tim Stevens

Published 15 January 2013

From Actin to Action

Emil Pai

Published 11 January 2013

Unstructured

A Brief History of CCP4

Published 12 December 2012

Stop, Collaborate and Listen

Eleanor Dodson

Published 5 November 2012

X-PLORer

Axel Brunger

Published 1 October 2012

Share the Wealth

Zbyszek Otwinowski

Published 22 August 2012

Unraveling RNA

Anna Pyle

Published 18 July 2012

Sharper Image

Pawel Penczek and SPARX

Published 4 June 2012

Creative Copy Cat

Pamela Bjorkman

Published 25 April 2012

Charm and Diplomacy

Gerard Kleywegt

Published 7 March 2012

From Curiosity to Cure

Marc Kvansakul

Published 13 December 2011

The Lure of the Sandbox

Paul Emsley and Coot

Published 15 October 2011

Springsteen, Tolkien, Protein

Alwyn Jones and Frodo

Published 17 June 2011

Structures Solved Simply

Paul Adams and Tom Terwilliger on Phenix

Published 2 June 2011

Escape from the Darkroom

Wolfgang Kabsch and XDS

Published 19 May 2011

Playing the Odds

Randy Read and Phaser

Published 19 May 2011

Better, Faster, Stronger, More

Victor Lamzin and ARP/wARP

Published 17 May 2011

Crystallography for Kids

Lynne Howell

Published 17 May 2011

Side-Track to Success

Ning Zheng

Published 13 May 2011