Blocking mitochondria's cleanup system made a standard leukemia drug work harder — in lab and mouse models

Venetoclax changed the treatment of acute myeloid leukemia (AML), especially for older patients who cannot tolerate intensive chemotherapy. But relapse is common, and research keeps pointing to the same escape route: mitochondria. Leukemic stem cells depend on mitochondrial energy production in a way healthy blood stem cells do not, and resistance to venetoclax is largely driven by mechanisms that regulate mitochondrial function.

A study published October 13, 2026 in Leukemia asked what happens if you attack the system leukemia cells use to maintain those mitochondria — mitophagy, the selective recycling of damaged mitochondria — at the same time as you give venetoclax.

What did the researchers test?

The team worked with a panel of AML cell lines, primary leukemia cells collected from 20 people newly diagnosed with AML, and healthy blood-forming cells for comparison. Using a fluorescent mitophagy reporter, they showed that the stress-sensor protein PINK1 — best known from Parkinson's disease research — is a key switch for mitophagy in leukemia cells: when mitochondria were stressed, PINK1 accumulated and mitophagy switched on, and removing PINK1 sharply reduced it. They also identified PHB2, a protein at the inner mitochondrial membrane, as part of how PINK1 is stabilized.

What happened when the cleanup system was blocked?

Leukemia cells deprived of PINK1 or PHB2 accumulated dysfunctional mitochondria with lower membrane potential and weaker oxygen consumption — their energy system degraded. Most importantly for treatment, inhibiting either protein significantly strengthened venetoclax's ability to eliminate leukemia cells, both in cell cultures and in mice carrying human leukemia xenografts. A drug that directly inhibits PHB2 produced the same boosting effect, which matters because it shows the target can be reached with a medicine-like molecule, not only with genetic tricks.

What does this mean for patients today?

Not yet a treatment — a direction. No PINK1 or PHB2 inhibitor has been tested in people with AML, and blocking mitophagy is a double-edged idea: healthy cells, especially neurons and heart cells, also depend on mitochondrial cleanup, so safety will be the central question for any drug program. What the study does establish is a concrete, testable combination strategy — venetoclax plus a mitophagy blocker — aimed squarely at the mitochondrial machinery that helps leukemia survive standard therapy.

Where the evidence stands

• Established: Venetoclax-based therapy is standard for older or unfit AML patients; leukemic stem cells depend on mitochondrial activity, and venetoclax resistance is primarily driven by mechanisms regulating mitochondrial function.
• Preliminary: In cell lines, primary cells from 20 patients, and mouse xenografts, inhibiting the mitophagy regulators PINK1 or PHB2 impaired mitochondrial function and significantly enhanced venetoclax's anti-leukemic effect in vitro and in vivo.
• Absent: Any human trial of a PINK1 or PHB2 inhibitor, safety data for blocking mitophagy in people, and evidence that this combination improves outcomes in patients.