Folding Under Pressure: How Living Cells Maintain Their Delicate Balance

Inside every living cell is a high-stakes balancing act that ensures proteins are made, folded, and discarded with precision. But what happens when this delicate system falters?

For Dr. Koyeli Mapa, a molecular biologist and Associate Professor at the Department of Life Sciences at Shiv Nadar Institution of Eminence, this is the question at the heart of her research.

Dr. Mapa works on what is known as “protein homeostasis” or proteostasis—the system by which cells ensure that proteins are correctly folded, functioning properly, and disposed of when no longer needed. When this system breaks down, it can lead to a toxic build-up of misfolded or aggregated proteins, a state known as proteotoxic stress. “Proteins must fold into particular three-dimensional structures to work,” explains Dr. Mapa. “But under stressful conditions like high temperatures or acidity, they can form abnormal folds and clump together, interfering with essential cellular functions.” This toxic buildup of harmful protein aggregates is now being recognized for its significant role in aging and neurodegenerative diseases such as Alzheimer’s Disease, Parkinson’s Disease, and amyotrophic lateral sclerosis (ALS).

Fortunately, cells are equipped with a mechanism to tackle this: a separate type of protein known as molecular chaperones. Dr. Mapa’s work is uncovering how this invisible but powerful quality-control system could hold clues to slowing down aging and neurodegeneration, along with identifying the molecular roots of disease.

Dr. Mapa’s fascination with this field began during her Ph.D., where she studied how proteins are transported into the mitochondria, which is the powerhouse of every cell. Mitochondria are unique as they are enclosed by two membranes and rely on thousands of proteins that are made elsewhere in the cell. This demands an extraordinary level of coordination and quality control, and molecular chaperones are critical to manage this task. To understand this better, Dr. Mapa dove deeper These proteins not only help other proteins fold, but in some cases, they also act as gatekeepers, deciding when and how a protein should be recycled. Her observations shed more light on the structure and molecular mechanism of chaperone function and dynamics, adding to the existing body of knowledge.

With yeast as a model, using genetics and biophysical assays, Dr. Mapa’s lab recently identified how specific areas within mitochondria handle protein folding stress. They focused on zones like the intermembrane space (IMS)—the space between the outer and inner membranes—and the matrix and discovered specialized molecules that help manage stress in these compartments.

An intriguing area of Dr. Mapa’s research explores how mitochondria “talk” to another vital organelle, the endoplasmic reticulum (ER). This cross-talk becomes especially critical during stress, when coordination between the two structures is vital to prevent cellular damage. “We know there are protein bridges called mitochondria-associated membranes or MAMs, that help them share resources like calcium and lipids. But what happens to these bridges under stress is still a mystery,” she says.

Dr. Mapa insists that while this body of work is complex and quite relevant, there are several gaps that need to be addressed through many more years of research before any real-life outcomes can materialize. For young scientists considering a career in molecular biology, her advice is simple: nurture curiosity and passion. “Science is 99% failure and 1% success,” she says, “but that 1% success is worth it.”

At its heart, Dr. Mapa’s work is about understanding the hidden and quiet cellular systems that keep life humming along. She points out, “Even with all this technology, biology remains full of mysteries. Sometimes we observe interesting phenomena happening in a cell, but we have no idea how to explain it. But this mystery keeps us going.”

And in the pursuit of those answers, the smallest proteins can tell the biggest stories. We look forward to seeing what Dr. Mapa and her team discover next!